Conditions: Tourette Syndrome
Keywords: Motor tics Vocal tics Cannabinoids Dronabinol PEA Palmitoylethanolamide Tourettes TS
Allocation: NA | Intervention model: SINGLE_GROUP
Enrollment: 17
Healthy volunteers: no

Brief summary:
This is an investigator-initiated proof of concept study with the purpose to examine the safety, tolerability and feasibility of Dronabinol (synthetic Δ9-THC) and PEA for the treatment of adults with Tourette syndrome.

Detailed description:
The investigators propose a 12-week, investigator-initiated, open-label trial of a therapeutic combination of Dronabinol and PEA in 18 adults with Tourette syndrome. Participants will receive Dronabinol and PEA in combination for the duration of the trial. The goal for this pilot study is to (1) provide initial safety, feasibility and tolerability data on both Dronabinol and PEA in a TS population and (2) provide data in order to make a more informed decision regarding the appropriate sample size and design of a larger clinical trial to prove efficacy (i.e. sample size and trial duration in large efficacy trial of the Dronabinol/PEA combination in TS).

Arms:
arm 1: All participants will be titrated up on Dronabinol dose during the first week of the trial (2.5mg Dronabinol for 3 days and then 5mg Dronabinol for 4 days increasing to 10mg Dronabinol for the remainder of the trial). Dronabinol will only be increased to 10mg at the week 1 assessment if the subject is tolerating the 5mg dose of Dronabinol and the Dronabinol may be reduced based on patient side-effects. All participants will receive two 400mg tablets of PEA daily for the same 12 weeks that they receive the Dronabinol.

Interventions: intervention 1: Dronabinol and Palmitoylethanolamide
Intervention descriptions: intervention 1: Participants will receive Dronabinol which will be slowly titrated in the first week of the study. They will be followed for a total of 12 weeks; in addition, participants will receive the PEA in a standing dose of 400mg. They will be followed for a total of 12 weeks.

Protocol document:
Prot_SAP_000.pdf: 
Titl e of R e s e ar c h Pr oj e ct:  
E x a mi ni n g t h e Effi c a c y of a T h er a p e uti c C o m bi n ati o n of Dr o n a bi n ol ( s y nt h eti c 9-
t etr a h y dr a c a n n a bi n ol) a n d P al mit o yl et h a n ol a mi d e f or T o ur ett e S y n dr o m e  
 
N C T 0 3 0 6 6 1 9 3  
I R B A p pr o v al D at e: 2 7 S e pt e m b er  2 0 1 7  


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YALE UNIVERSITY
HUMAN INVESTIGATION COMMITTEE
Application to Involve Human Subjects in Biomedical Research 
100 FR1 (2015-2)
SECTION I: ADMINISTRATIVE INFORMATION
Title of Research Project:
Examining the Efficacy of a Therapeutic Combination of Dronabinol (synthetic 9-tetrahydracannabinol) and 
Palmitoylethanolamide for Tourette Syndrome
Principal Investigator:
Michael H. Bloch, MD, MS
Yale Academic Appointment:
Associate Professor
Department: Child Study Center
Campus Address:
230 South Frontage Rd., New Haven, CT 06520 NIHB-205
Campus Phone: 203-745-9921
Fax: 203-785-7611
Pager: 203-745-9921
E-mail:
Michael.bloch@yale.edu
Protocol Correspondent Name & Address (if different than PI):
Angeli Landeros-Weisenberger, MD, 230 South Frontage Rd, New Haven, CT 06520 SHM-I-371
Campus Phone: 203-737-4809
Fax: 203-737-5104
E-mail: angeli.landeros@yale.edu
Yale Cancer Center CTO Protocol Correspondent Name & Address (if applicable):
Campus Phone:
Fax:
E-mail:
Business Manager:
Campus Phone :
Fax :
E-mail
tment:
 
 
Investigator Interests:
Does the principal investigator, or do any research personnel who are responsible for the design, 
conduct or reporting of this project or any of their family members (spouse or dependent child) 
have an incentive or interest, financial or otherwise, that may affect the protection of the human 
subjects involved in this project, the scientific objectivity of the research or its integrity? Note: 
The Principal Investigator (Project Director), upon consideration of the individual’s role and 
degree of independence in carrying out the work, will determine who is responsible for the 
design, conduct, or reporting of the research.
Faculty Advisor:(required if PI is a student, 
resident, fellow or other trainee)
NA
Campus Address:
Campus Phone:
Fax:
Pager:
E-mail:
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See Disclosures and Management of Personal Interests in Human Research  
http://www.yale.edu/hrpp/policies/index.html#COI
 Yes
 No
Do you or does anyone on the research team who is determined by you to be responsible for the 
design, conduct or reporting of this research have any patent (sole right to make, use or sell an 
invention) or copyright (exclusive rights to an original work) interests related to this research 
protocol?
 Yes
 No
If yes to either question above, list names of the investigator or responsible person:
The Yale University Principal Investigator, all Yale University co-investigators, and all Yale 
University individuals who are responsible for the design, conduct or reporting of research must 
have a current financial disclosure form on file with the University’s Conflict of Interest Office. 
Yale New Haven Hospital personnel who are listed as co-investigators on a protocol with a Yale 
University Principal Investigator must also have a current financial disclosure form on file with 
the University’s Conflict of Interest Office. If this has not been done, the individual(s) should 
follow this link to the COI Office Website to complete the form: http://www.yale.edu/coi/
NOTE: The requirement for maintaining a current disclosure form on file with the University’s 
Conflict of Interest Office extends primarily to Yale University and Yale-New Haven Hospital 
personnel.  Whether or not they are required to maintain a disclosure form with the 
University’s Conflict of Interest Office, all investigators and individuals deemed otherwise 
responsible by the PI who are listed on the protocol are required to disclose to the PI any 
interests that are specific to this protocol.
SECTION II: GENERAL INFORMATION
1. Performing Organizations:  Identify the hospital, in-patient or outpatient facility, school or 
other agency that will serve as the location of the research. Choose all that apply:
a. Internal Location[s] of the Study:
Magnetic Resonance Research Center
Yale University PET Center
(MR-TAC)
YCCI/Church Street Research Unit (CSRU) 
Yale Cancer Center/Clinical Trials Office (CTO)
YCCI/Hospital Research Unit (HRU)
Yale Cancer Center/Smilow
YCCI/Keck Laboratories
Yale-New Haven Hospital
Yale-New Haven Hospital—Saint Raphael Campus 
Cancer Data Repository/Tumor Registry
Specify Other Yale Location: Yale Child Study Center
b. External Location[s]:
APT Foundation, Inc.
Haskins Laboratories 
Connecticut Mental Health Center
John B. Pierce Laboratory, Inc.
Clinical Neuroscience Research Unit (CNRU)
Veterans Affairs Hospital, West Haven 
Other Locations, Specify:
International Research Site
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(Specify location(s)):
c. Additional Required Documents (check all that apply):
N/A
*YCCI-Scientific and Safety Committee (YCCI-SSC)
Approval Date:
*Pediatric Protocol Review Committee (PPRC)
Approval Date:
*YCC Protocol Review Committee (YRC-PRC)
Approval Date:
*Dept. of Veterans Affairs, West Haven VA HSS
Approval Date:
*Radioactive Drug Research Committee (RDRC)
Approval Date: 
YNHH-Radiation Safety Committee (YNHH-RSC)
Approval Date: 
Yale University RSC (YU-RSC)
Approval Date: 
Magnetic Resonance Research Center PRC (MRRC-PRC)     Approval Date:
*Nursing Research Committee
Approval Date:
YSM/YNHH Cancer Data Repository (CaDR)
Approval Date: 
Dept. of Lab Medicine request for services or specimens form
Imaging on YNHH Diagnostic Radiology equipment request form (YDRCTO request) found 
at http://radiology.yale.edu/research/ClinTrials.aspx)
*Approval from these committees is required before final HIC approval is granted. See instructions 
for documents required for initial submission and approval of the protocol. Allow sufficient time for 
these requests. Check with the oversight body for their time requirements.
2. Probable Duration of Project: State the expected duration of the project, including all 
follow-up and data analysis activities.
3 years
3. Research Type/Phase: (Check all that apply)
a. Study Type
Single Center Study 
Multi-Center Study
Does the Yale PI serve as the PI of the multi-site study? Yes
No 
Coordinating Center/Data Management
Other:
b. Study Phase
N/A
Pilot
Phase I
Phase II
Phase III
Phase IV 
Other (Specify)
4. Area of Research: (Check all that apply) Note that these are overlapping definitions and 
more than one category may apply to your research protocol. Definitions for the following 
can be found in the instructions section 4c:
Clinical Research: Patient-Oriented
Clinical Research: Outcomes and 
Clinical Research: Epidemiologic and Behavioral
Health Services 
Translational Research #1 (“Bench-to-Bedside”)
Interdisciplinary Research 
Translational Research #2 (“Bedside-to-Community”)
Community-Based Research
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5. Is this study a clinical trial? Yes
No
NOTE the current ICMJE (International Committee of Medical Journal Editors) definition of a 
clinical trial: “any research study that prospectively assigns human participants or groups of humans 
to one or more health-related interventions to evaluate the effects on health outcomes.” Health-related 
interventions include any intervention used to modify a biomedical or health-related outcome (for 
example, drugs, surgical procedures, devices, behavioral treatments, dietary interventions, and 
process-of-care changes). Health outcomes include any biomedical or health-related measures 
obtained in patients or participants, including pharmacokinetic measures and adverse events”
If yes, where is it registered?
Clinical Trials.gov registry 
Other (Specify)
Registration of clinical trials at their initiation is required by the FDA, NIH and by the ICMJE.
If this study is registered on clinicaltrials.gov, there is new language in the consent form and compound 
authorization that should be used.
For more information on registering clinical trials, including whether your trial must be 
registered, see the YCCI webpage, http://ycci.yale.edu/researchers/ors/registerstudy.aspx 
or contact YCCI at 203.785.3482)
6. Does the Clinical Trials Agreement (CTA) require compliance with ICH GCP (E6)? 
Yes
No
7. Will this study have a billable service? A billable service is defined as any service rendered to 
a study subject that, if he/she was not on a study, would normally generate a bill from either 
Yale-New Haven Hospital or Yale Medical Group to the patient or the patient’s insurer. The 
service may or may not be performed by the research staff on your study, but may be provided by 
professionals within either Yale-New Haven Hospital or Yale Medical Group (examples include 
x-rays, MRIs, CT scans, specimens sent to central labs, or specimens sent to pathology). Notes:
1. There is no distinction made whether the service is paid for by the subject or their insurance 
(Standard of Care) or by the study’s funding mechanism (Research Sponsored). 2. This generally 
includes new services or orders placed in EPIC for research subjects.
Yes
No
If answered, “yes”, this study will need to be set up in OnCore, Yale’s clinical research 
management system, for Epic to appropriately route research related charges. Please contact  
oncore.support@yale.edu
8.. Are there any procedures involved in this protocol that will be performed at YNHH or one of 
its affiliated entities?  Yes
No X If Yes, please answer questions a through c and note 
instructions below.  If No, proceed to Section III.
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a. Does your YNHH privilege delineation currently include the specific procedure that you will 
perform?
b. Will you be using any new equipment or equipment that you have not used in the past for 
this procedure?
c. Will a novel approach using existing equipment be applied?
If you answered “no” to question 8a, or "yes" to question 8b or c, please contact the YNHH 
Department of Physician Services (688-2615) for prior approval before commencing with your 
research protocol.
Please note that if this protocol includes Yale-New Haven Hospital patients, including patients at 
the HRU, the Principal Investigator and any co-investigators who are physicians or mid-level 
practitioners (includes PAs, APRNs, psychologists and speech pathologists) who may have direct 
patient contact with patients on YNHH premises must have medical staff appointment and 
appropriate clinical privileges at YNHH. If you are uncertain whether the study personnel meet 
the criteria, please telephone the Physician Services Department at 203-688-2615. By signing 
this protocol as a PI, you attest that you and any co-investigator who may have patient contact 
has a medical staff appointment and appropriate clinical privileges at YNHH.
SECTION III: FUNDING, RESEARCH TEAM AND TRAINING
1. Funding Source: Indicate all of the funding source(s) for this study. Check all boxes that apply. 
Provide information regarding the external funding source.  This information should include 
identification of the agency/sponsor, the funding mechanism (grant or contract), and whether 
the award is pending or has been awarded. Provide the M/C# and Agency name (if grant- 
funded).  If the funding source associated with a protocol is “pending” at the time of the 
protocol submission to the HIC (as is the case for most NIH submissions), the PI should note 
“Pending” in the appropriate section of the protocol application, provide the M/C# and 
Agency name (if grant-funded) and further note that University (departmental) funds support 
the research (until such time that an award is made).
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PI
Title of Grant
Name of Funding Source
Funding
Funding Mechanism
Michael H. 
Bloch, MD, MS
Examining the 
Efficacy of a 
Therapeutic 
Combination of 
Dronabinol (synthetic
9- 
tetrahydracannabinol) 
and 
Palmitoylethanolamide 
for Adults with 
Tourette Syndrome
Therapix Biosciences 
Ltd.
P
Federal
State
Non Profit 
Industry 
Other For
rofit
Other
I
Grant-M#
Contract# 
Contract Pending
Investigator/Department 
nitiated
Sponsor Initiated 
Other, Specify:
P
Federal
State
Non Profit 
Industry 
Other For
rofit
Other
I
Grant-M#
Contract# 
Contract Pending
Investigator/Department 
nitiated
Sponsor Initiated 
Other, Specify:
P
Federal
State
Non Profit 
Industry 
Other For
rofit
Other
I
Grant-M#
Contract# 
Contract Pending
Investigator/Department 
nitiated
Sponsor Initiated 
Other, Specify:
IRB Review fees are charged for projects funded by Industry or Other For-Profit Sponsors. 
Provide the Name and Address of the Sponsor Representative to whom the invoice should be 
sent.  Note: the PI’s home department will be billed if this information is not provided.
Send IRB Review Fee Invoice To:
Name: Dr. Adi Zuloff-Shani, PhD 
Company: Therapix Biosciences Ltd.
Address: 5 Azrieli Center (Square Tower) 27 Fl., Tel-Aviv 6702501, Israel
2. Research Team:  List all members of the research team. Indicate under the affiliation column whether 
the investigators or study personnel are part of the Yale faculty or staff, or part of the faculty or staff 
from a collaborating institution, or are not formally affiliated with any institution. ALL members of 
the research team MUST complete Human Subject Protection Training (HSPT) and Health 
Insurance Portability and Accountability Act (HIPAA) Training before they may be listed on the 
protocol. See NOTE below.
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NOTE: The HIC will remove from the protocol any personnel who have not completed required training.
Name
Affiliation: Yale/Other 
Institution (Identify)
NetID
Principal Investigator
Michael H. Bloch, MD, MS
Yale
MHB32
Role: Co-Investigator
James F. Leckman, MD
Yale
JFL2
Role: Co-Investigator
Angeli Landeros-Weisenberger, MD
Yale
ALW495
Role: Study Personnel
Jessica A. Johnson, BS
Yale
JAJ62
Role: Study Personnel
Shilpa Telang, M.D.
Yale
SB2558
Role: Study Personnel
Baris Olten, M.D.
Yale
BO222
A personnel protocol amendment will need to be submitted when training is completed.
SECTION IV:
PRINCIPAL INVESTIGATOR/FACULTY ADVISOR/ DEPARTMENT CHAIR AGREEMENT
As the principal investigator of this research project, I certify that:

The information provided in this application is complete and accurate.

I assume full responsibility for the protection of human subjects and the proper conduct of the 
research.

Subject safety will be of paramount concern, and every effort will be made to protect subjects’ 
rights and welfare.

The research will be performed according to ethical principles and in compliance with all federal, 
state and local laws, as well as institutional regulations and policies regarding the protection of 
human subjects.

All members of the research team will be kept apprised of research goals.

I will obtain approval for this research study and any subsequent revisions prior to my initiating the 
study or any change and I will obtain continuing approval of this study prior to the expiration date 
of any approval period.

I will report to the HIC any serious injuries and/or other unanticipated problems involving risk to 
participants.

I am in compliance with the requirements set by the University and qualify to serve as the 
principal investigator of this project or have acquired the appropriate approval from the 
Dean’s Office or Office of the Provost, or the Human Subject Protection Administrator at 
Yale-New Haven Hospital, or have a faculty advisor.

I will identify a qualified successor should I cease my role as principal investigator and facilitate a 
smooth transfer of investigator responsibilities.
_Michael H. Bloch, MD, MS
10/06/16 
 
PI Name (PRINT) and Signature
Date
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As the faculty advisor of this research project, I certify that:

The information provided in this application is complete and accurate.

This project has scientific value and merit and that the student or trainee investigator has the necessary 
resources to complete the project and achieve the aims.

I will train the student investigator in matters of appropriate research compliance, protection of human 
subjects and proper conduct of research.

The research will be performed according to ethical principles and in compliance with all federal, state and 
local laws, as well as institutional regulations and policies regarding the protection of human subjects.

The student investigator will obtain approval for this research study and any subsequent revisions prior to 
initiating the study or revision and will obtain continuing approval prior to the expiration of any approval 
period.

The student investigator will report to the HIC any serious injuries and/or other unanticipated 
problems involving risk to participants.

I am in compliance with the requirements set forth by the University and qualify to serve as
the faculty 
advisor of this project.

I assume all of the roles and responsibilities of a Principal Investigator even though the student may be 
called a PI.
Advisor Name (PRINT) and Signature
Date
Department Chair’s Assurance Statement
Do you know of any real or apparent institutional conflict of interest (e.g., Yale ownership of a 
sponsoring company, patents, licensure) associated with this research project?
Yes (provide a description of that interest in a separate letter addressed to the HIC.) 
No
As Chair, do you have any real or apparent protocol-specific conflict of interest between yourself and 
the sponsor of the research project, or its competitor or any interest in any intervention and/or method 
tested in the project that might compromise this research project?
Yes (provide a description of that interest in a separate letter addressed to the HIC) 
No
I assure the HIC that the principal investigator and all members of the research team are qualified by 
education, training, licensure and/or experience to assume participation in the conduct of this research 
trial. I also assure that the principal investigator has departmental support and sufficient resources to 
conduct this trial appropriately.
Chair Name (PRINT) and Signature
Date
Department
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YNHH Human Subjects Protection Administrator Assurance Statement
Required when the study is conducted solely at YNHH by YNHH health care providers.
As Human Subject Protection Administrator (HSPA) for YNHH, I certify that:

I have read a copy of the protocol and approve it being conducted at YNHH.

I agree to notify the IRB if I am aware of any real or apparent institutional conflict of interest.

The principal investigator of this study is qualified to serve as P.I. and has the support of the hospital 
for this research project.
YNHH HSPA Name (PRINT) and Signature
Date
SECTION V: RESEARCH PLAN
1. Statement of Purpose: State the scientific aim(s) of the study, or the hypotheses to be tested.
This is an investigator-initiated proof of concept study with the purpose to examine the safety, 
tolerability and feasibility of Dronabinol (synthetic 9-THC) and PEA for the treatment of adults 
with Tourette syndrome.
2. Background: Describe the background information that led to the plan for this project. 
Provide references to support the expectation of obtaining useful scientific data.
Tourette syndrome (TS) affects slightly less than 1% of school-age children and 0.5% adults.(1) The 
tics associated with TS can have significant effects on the academic and social development of children as 
well as affecting their overall self-esteem and mental health. Although the majority of children experience 
a decrease in their tics during adolescence, the worst symptoms are usually experienced by adults with 
intractable TS.(2, 3)
There are significant limitations to the available treatments for TS in terms of both efficacy and 
side-effects. Currently, two antipsychotic agents are the only FDA-approved medications for TS: 
haloperidol and pimozide. Atypical antipsychotic agents are also widely utilized in the treatment of TS even 
though only risperidone has demonstrated efficacy in multiple, placebo-controlled clinical trials.(4-6) 
Antipsychotic agents, although the most effective agent in reducing tics, are not utilized as a first-line 
treatment for tics (especially in children) because of the significant side-effects associated with their use.(4-
6)  New treatments for TS are urgently needed.
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Figure 2: Diagram of CB1 role in Dopaminergic 
Motor Circuits of Basal Ganglia. GABAergic 
inhibitory pathways are represented in blue and 
glutamatergic excitatory pathways in red. Modulatory 
dopaminergic connections are indicated in green.
CB1, cannabinoid receptor type 1; TRPV1, transient 
receptor potential vanilloid type 1; D1, dopaminergic 
receptor type 1; D2, dopaminergic receptor type 2; 
GPe, external globus pallidus; GPi, internal globus 
pallidus; STN, subthalamic nucleus; SNpc, substantia 
nigra pars compacta; SNpr, substantia nigra pars 
reticulata. [13]
Several 
lines 
of 
evidence 
suggest 
that 
cannabis 
(Cannabis 
sativa) 
and 
9- 
tetrahydracannabinol (9-THC) may be effective in the treatment of tic disorders. Anecdotal case 
reports have long suggested that smoking marijuana may improve tic symptoms.(7-9) Standardized 
interviews of 64 consecutive TS patients seeking treatment in Germany reported that 82% of TS patients 
experienced a reduction or complete remission of tic symptoms when smoking cannabis.(10) 9- 
tetrahydracannabinol (9-THC), the principal active constituent of cannabis has been studied in 
randomized, placebo-controlled trials in TS.(10) A double-blind, placebo-controlled crossover trial of 5- 
10mg of 9-THC in 12 adults with TS, demonstrated a significant reduction in measures of tic severity and 
global improvement with 9-THC compared to placebo. Tourette syndrome Symptom List (TSSL) ratings 
of tic severity were significantly reduced when subjects were given 9-THC (12.511.0 point) compared 
to placebo (2.57.0 points) (p=0.015).(11) A 6-week, double-blind, placebo-controlled trial of 24 adults 
with TS also demonstrated a significant benefit of 9-THC compared to placebo. Figure 1 depicts the 
change in TSSL scores during the course of the 6-week trial. Subjects randomly assigned to 9-THC 
experienced significant reduction of their tic symptoms compared to placebo after the first 2 weeks of 
treatments        that        continued
throughout the 6-week trial. These 
improvements 
vanished 
when 
subjects 
discontinued 
9- 
THC.(12) The treatment effect 
size observed for 9-THC was 
considerably 
larger 
than 
that 
observed in placebo-controlled 
trials 
of 
currently 
available 
treatments for TS.
CB1 receptors may be involved in the pathophysiology of 
TS: Biological evidence also suggests that the brain cannabinoid 
system may contribute to the pathophysiology of TS and other 
movement disorders.(13, 14) CB1 receptors and endocannabinoids 
are highly expressed in the basal ganglia and appear to have an 
important role in modulating dopaminergic motor circuits.(14) 
Specifically CB1 receptors are expressed presynaptically on 
medium-spiny neurons -- striatal neurons projecting in both the 
direct (substantia nigra pars reticulata and the globus pallidus pars 
interna) and indirect (globus pallidus pars externa) pathways.(15) 
Activation of CB1 receptors in combination with D1 receptors of 
the direct pathway serves to decrease adenyl cyclase release within 
projection neurons. By contrast, activation of CB1 receptors in 
combination with D2 receptors serves to stimulate adenyl cyclase 
in projection neurons of the indirect pathway.(14) Figure 2 
illustrates the mechanisms by which endocannabinoids play an 
important role in motor inhibition. Although CB1 receptors are 
not expressed by most striatal GABAergic interneurons, CB1 
receptors are expressed by parvalbumin positive interneurons and 
some cholinergic interneurons.(15) Parvalbumin positive and 
cholinergic striatal interneurons have been demonstrated to be 
significantly reduced in post mortem studies of TS patients.(16)
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The major limitations of both cannabis and dronabinol use, is the adverse psychoactive side effects, 
they induce in higher doses. The psychoactive effects of 9-THC are primarily mediated by its activation 
of CB1G-protein coupled receptors, which result in a decrease in the concentration of the second messenger 
molecule cAMP through inhibition of adenylate cyclase (3). Thus, in order to harness the therapeutic 
potential of 9-THC for patients with Tourette's syndrome, there is a need to reduce the accompanied 
adverse effects.
We hope to use the entourage effect to deliver the therapeutic benefits of Dronabinol (synthetic
9-THC) in reducing tics with decreased psychoactive effects using Palmitoylethanolamide (PEA). The 
basic idea of the entourage effect is that cannabinoids within the cannabis plant work together, or possess 
synergy, and affect the body in a mechanism similar to the body’s own endocannabinoid system. 
Palmitoylethanolamide (PEA) is a lipid messenger known to mimic several endocannabinoid-driven 
activities although it does not bind the classical CB receptors. Based on an activity enhancement of other 
physiological compounds, by potentiating their affinity for a receptor or by inhibiting their metabolic 
degradation, PEA may indirectly stimulate the effects of both phyto- or endocannabinoids, either by its role 
as an agonist of the transient receptor potential vanilloid type 1 (TRPV1), peroxisome proliferator-activated 
receptor-α (PPAR-α) and the cannabinoid receptors(6). PEA capacity to exert 'entourage effects' is derived 
from its ability to affect multiple targets within the body, to improve the absorption of active ingredients 
and to minimize adverse side effects (7).
One of the most important compounds to be affected by PEA is endocannabinoid anandamide 
(AEA). Sub-effective dose of AEA, when co-injected with PEA, significantly decreases blood pressure. 
PEA also enhances the hypotensive responses to both AEA and meth AEA (8). AEA induces vasorelaxation 
only in the presence of PEA, and the PEA potentiating occurs through TRPV1 receptors. The discovery of 
anandamide came from research into CB1 and CB2, as it was inevitable that a naturally occurring 
(endogenous) chemical would be found to affect these receptors. As PEA potentiate the effect of AEA, it 
is plausible to assume it may exert the same effect on cannabis derived phytocannabinoids such as 9-THC. 
In a murine model of behavioral and pain perception it was shown that addition of PEA to THC reduced 
the deleterious behavioural side effects of THC and potentiate the analgesic effect of THC sub-effective 
dose (Brener et al, 26th symposium of the ICRS, 2016)
PEA has been shown to possess anti-craving effects in cannabis dependent patients, is efficacious in 
the treatment of withdrawal symptoms, produces a reduction of cannabis consumption and is effective in 
the prevention of cannabis induced neurotoxicity and neuro-psychiatric disorders. Moreover, by combining
9-THC therapy with PEA, one can overcome the over-sensitization/irritation that the 9-THC alone causes 
to the respiratory tract, by PEA ability to stabilize mucosal mast cells and prevent their degranulation. Thus 
combination of 9-THC with PEA, may be proved to be by far more safe and effective than 9-THC alone.
Dronabinol:
Dronabinol is a cannabinoid designated chemically as (6aR-trans)6a,7,8,10a-tetrahydro-6,6,9-trimethyl-3- 
pentyl-6H-dibenzo[b,d]pyran-1-ol. CAS registry number 1972-08-03.
Dronabinol is the INN for a pure isomer of THC, (-)-trans-Δ9-tetrahydrocannabinol and is the active 
ingredient in dronabinol capsules, is synthetic delta-9tetrahydrocannabinol (delta-9-THC). Delta-9- 
tetrahydrocannabinol is also a naturally occurring component of Cannabis sativa L. (Marijuana).
Synthesized dronabinol is marketed as Marinol (a registered trademark of Solvay Pharmaceuticals). 
Dronabinol is also marketed, sold and distributed by PAR Pharmaceutical Companies under the terms of a 
license and distribution agreement with SVC pharma LP, an affiliate of Rhodes Technologies.
. 9-THC is the primary psychoactive component of the Cannabis plant, and is the most notable 
cannabinoid. 9-THC possesses activities as a psychoactive agent, analgesic,  muscle relaxant, 
antispasmodic, bronchodilator, neuroprotective antioxidant and antipruritic agent.
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9-THC has affinity to both CB1 and CB2 classical cannabinoid receptors. Classical cannabinoid receptors 
(CB1 and CB2) are 7 transmembrane G-protein couple receptors (known as GPCRs) negatively coupled to 
adenylyl cyclase and positively coupled to MAPKs such as extracellular signal related kinases 1 and 2 
(ERK1/2) through Gi/o proteins (17). CB1 is highly expressed in neurons within the hippocampus, basal 
ganglia, cerebellum, cortex, thalamus and periaqueductal gray but poorly expressed in the respiratory center 
of the brainstem, hence the reason for lack of respiratory depression seen with cannabis toxicity. CB2 is 
expressed on immunocytes including microglia and mast cells. CB2 is poorly expressed in the CNS (100- 
fold lower expression than CB1) but rapidly upregulated in microglia and neurons with neural injury and 
inflammation (18).
In the United States, Marinol is a Schedule III drug, available by prescription, considered to be non-narcotic 
and to have a low risk of physical or mental dependence. Marinol has been approved in US and in Canada 
in the treatment of anorexia in AIDS patients (19-21), as well as for refractory nausea and vomiting of 
patients undergoing chemotherapy 19,22,24). It was proved as safe and effective for these uses (19).
Nabiximols (Sativex) is a combination of Cannabidiol (CBD) and THC (at a ratio of 1:1). This product was 
approved in Canada as a mouth spray to alleviate neuropathic pain, spasticity, overactive bladder, and other 
symptoms of multiple sclerosis. This product is also approved in additional countries in Europe (including 
UK) as well as Israel.
9-THC was investigated in additional clinical studies evaluating its use in a variety of clinical indications 
other than the approved ones (see Appendix 1) (20-22). These include evaluation of 9-THC efficacy on 
pain reduction in different patient’s populations (multiple sclerosis (23), amyotrophic lateral sclerosis 
(ALS) (24), fibromyalgia (25), cancer, abdominal hysterectomy (26), headaches (27), spinal cord injury, 
and muscle spasticity), obstructive sleep apnea (28), internal pressure in end-stage open-angle glaucoma 
(29, 30), dementia-related neuropsychiatric symptoms (NPS), progressive inflammatory brain disease, 
antiemetic effect, colonic motility and sensation.
In MS patients, the effect of 9-THC on various symptoms (such as muscle spasticity, illness progression, 
and urge incontinent episodes) was also investigated in different clinical trials. In cancer patients, the effects 
of 9-THC on chemosensory alterations, appetite, quality of life and anorexia were also investigated. Side- 
effects associated with 9-THC include mood changes, dizziness, drowsiness, confusion, trouble 
concentrating, feeling "high," warmth or tingly feeling, an exaggerated sense of well-being, anxiety, 
lightheadedness, headache, red eyes, dry mouth, nausea, vomiting, stomach pain, diarrhea, sleep problems 
(insomnia), clumsiness, lack of coordination, weakness, unsteadiness or insomnia. Serious, uncommon 
side-effects associated with 9-THC include seizure, paranoia, disorganized/unusual behavior and 
tachycardia.(31)
PEA:
PEA is a primary fatty acid amide found in egg yolk, and as such, it falls under the definition of “egg 
yolk-derived phospholipids” (As an ingredient in term and preterm infant formula), which are listed as 
GRAS ingredients (GRN No. 411). Furthermore, PEA can be considered as a derivate of fatty acid ethyl 
ester (from anchovy or menhaden oil), which are listed as GRAS ingredient (GRN No. 494).
PEA content can also be attributed to FDA List of Indirect Additives Used in Food Contact Substances 
under general Main Term: ANIMAL OIL FATTY ACID AMIDES, Doc No. 7625, CAS RN 977139-08-
4. In addition, PEA is listed under the Code of Federal Regulations Title 21, 21CFR175.105 (Revised as 
of April 1, 2014) SUBCHAPTER B--FOOD FOR HUMAN CONSUMPTION PART 175 -- INDIRECT 
FOOD ADDITIVES: ADHESIVES AND COMPONENTS OF COATINGS.
In Europe, PEAPure is categorized as food supplement and marketed as such. Other PEA derived 
products (Normast® and Pelvilen®) are approved via a decentralized procedure in few EU countries 
(Italy, Spain, Slovakia, Germany and the Netherlands) as a food for medical purposes.
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An additional PEA product (Palmidrol) has been approved nationally in Spain and Italy as an anti- 
inflammatory agent (CAS 0000544-31-0).
Clinical research on PEA started in the 1960s and 1970s, especially in the Czech Republic. PEA, at that 
time under the brand name ‘Impulsin’ was indicated for prevention of flu and respiratory diseases and 
immune system enhancement (32-36). In general, PEA has been shown to be effective, tolerable and safe. 
PEA has been submitted for clinical relevancy as an analgesic, as a treatment for various chronic pain states. 
More than 30 various clinical trials have been conducted, shedding light on clinical relevance of PEA as a 
standalone agent or as a part of combinational therapy. It is of high importance that these trials demonstrate 
no relevant side-effects and no drug-drug interactions, when PEA has been administered. Full range of PEA 
doses had been implemented, most notably 300 mg or 600 mg for up to two times a day (1200 mg/day) and 
up to two months. PEA has been found to be effective in many pain states. Clinically addressed pain states 
include refractory neuropathic pain, temporomandibular joint disorder (TMJD), Costen syndrome, pains 
due to lumbosciatic problems, low back pain, diabetes-induced carpal tunnel syndrome, entrapment 
neuropathy (with significant improvement in neurophysiological parameters (distal motor latency)).
When used in combination with other agents, such as Pregabalin (Lyrica, Pfizer), classical NSAIDs, 
transpolydatin or oxycodone, PEA has been found to potentiate the analgesic effect of the mentioned drugs. 
Efficacy of PEA as part of multimodal analgesic therapy in patients with low back pain has been 
demonstrated. PEA enhances the analgesic effects of other compounds. Visual, analog scale (VAS) is a 
psychometric response scale which can be used in questionnaires, has been found to lower from 7 to mean
2.5 in most cases of PEA use. All neurophysiological parameters improved on PEA. In patients suffering 
from MS and neuropathic pain and treated with PEA 300 mg twice daily, 14 of 20 patients were full 
responders. Significant decrease of spasticity (as measured via modified Ashworth scale) and pain after 
stroke due to treatment with PEA was also observed. PEA improves pain and nerve function in patients 
suffering from chemotherapy induced neuropathy. Pain significantly decreased and nerve function, as 
measured by laser evoked LEP, increased significantly. In 20 patients undergoing thalidomide and 
bortezomib treatment for multiple myeloma, changes in neurophysiological measures indicate that PEA 
exerted a positive action on myelinated fiber groups. PEA, possibly by moderating mast cell hyperactivity, 
relieved conduction blocks secondary to endoneural edema. In a severe condition such as painful 
neuropathy associated with multiple myeloma and chemotherapy, a safe substance such as PEA provides 
significant restoration of nerve function. In glaucoma patients, PEA effects have been investigated on 
intraocular pressure (IOP) in primary open angle glaucoma (POAG) and ocular hypertension (OH). 
Systemic administration of PEA reduces IOP in patients with glaucoma and ocular hypertension. PEA could 
be a valuable tool for the treatment of glaucoma.
Moreover, PEA based topical treatment for conditions such as atopic eczema, atopic dermatitis, contact 
allergic dermatitis, facial post-herpetic neuralgia and pruritus have shown to be an effective remedy. PEA 
based creams inhibit ultraviolet light-induced inflammation and DNA damage in human skin. PEA as an 
analgesic can be utilized in dentistry and has been used in study for Impacted Lower Third Molar Surgery. 
Administering PEA improves the postoperative course—in terms of pain—after lower third molar 
extraction.
Thus, PEA treatments by means of oral (systemic) or topical administration prove to be effective and safe, 
with no observable side effects, and no noticed drug-drug interactions. Appendix 2 provides a 
comprehensive list of previous trials conducted using PEA. In these trials no adverse events have been 
reported that exceed the rate observed with placebo controls.
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3. Research Plan: Summarize the study design and research procedures using non-technical 
language that can be readily understood by someone outside the discipline. Be sure to 
distinguish between standard of care vs. research procedures when applicable, and 
include any flowcharts of visits specifying their individual times and lengths. Describe 
the setting in which the research will take place.
Overview
We propose a 12-week, investigator-initiated, open-label trial of a therapeutic combination of Dronabinol 
and PEA in 18 adults with Tourette syndrome. Subjects will receive Dronabinol and PEA in combination 
for the duration of the trial. Our goal for this pilot study is to (1) provide initial safety, feasibility and 
tolerability data on both Dronabinol and PEA in a TS population and (2) provide data in order to make a 
more informed decision regarding the appropriate sample size and design of a larger clinical trial to prove 
efficacy (i.e. sample size and trial duration in large efficacy trial of the Dronabinol/PEA combination in 
TS).
Subjects
Eighteen adults will be recruited through the TS/OCD Clinic at the Yale Child Study Center. The Yale 
Child Study Center has a nearly three-decade history of successfully recruiting for pharmacological trials 
of TS. We will additionally recruit through email blast through local TS chapters and by contacting local 
providers who treat adults with TS. We will additionally contact adult subjects who recently completed 
other treatment trials for TS at our site and agreed to be contacted for future trials. Subjects will be 
compensated $500 for their participation.
Interventions
Subjects will be titrated up on Dronabinol dose during the first week of the trial (2.5mg Dronabinol for 3 
days and then 5mg Dronabinol for 4 days increasing to 10mg Dronabinol for the remainder of the trial). 
Dronabinol will only be increased to 10mg at the week 1 assessment if the subject is tolerating the 5mg 
dose of Dronabinol and the Dronabinol may be reduced based on patient side-effects. Subjects will be 
assigned to receive two 400mg tablets of PEA daily for all 12 weeks. See pages 9-12 of this application 
for a detailed description of previous human use, known risks, and data addressing dosage(s), interval(s), 
route(s) of administration, and any other factors that might influence risks for both Dronabinol and PEA.
Assessments
Pre-study screening procedure: After an initial phone screen to rule out obvious exclusions from the study 
protocol, potential subjects will have an initial evaluation that will be performed by a multidisciplinary 
clinical team. In addition to a standard clinical evaluation consisting of history, and mental status exam, 
subjects will receive a clinical diagnostic interview using the Structured Clinical Interview of DSM-IV 
(SCID). Additional rating scales will assess severity of tic symptoms and common comorbid symptoms 
such as OCD, ADHD, depression and anxiety severity which are listed below.
Baseline Assessments
Medical Assessments
Rating scales
SCID
Psychiatric History 
General Medical History 
Chart review of Med Hx
Vital Signs, ECG 
Physical Exam 
Mental Status Exam 
Baseline Labs
Urine Tox and Preg.
YGTSS
PUTS
Y-BOCS
Connors 
HAM-D
HAM-A 
CGI
AERS 
TSSL
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Outcome Measures:

Improvement in Tic Severity -- Yale Global Tic Severity Scale (YGTSS) (Total Tic Score)

Improvement of Premonitory Urges -- Premonitory Urge for Tics Scale (PUTS)

Self-Report of Tic Severity – Tourette Syndrome Symptom List (TSSL)

OCD Severity -- Yale-Brown Obsessive-Compulsive Scale (Y-BOCS)

ADHD severity -- Connors Adult Attention Deficit Hyperactivity Rating Scale (Connors)

Depression Severity-- Hamilton Rating Scale for Depression (HAM-D)

Anxiety Severity -- Hamilton Rating Scale for Anxiety (HAM-A)

Overall Improvement -- Clinical Global Improvement Scale (CGI)

Adverse Effects -- Adverse Events Rating Scale (AERS)
Safety Assessments:
A medical assessment including vital signs, ECG, physical exam, routine blood tests indicating physical 
health and urine drug screen and pregnancy test will be completed prior to study enrollment. These safety 
assessments will be repeated every 2 weeks throughout the trial. Additionally, subjects will be assessed for 
any adverse effects of medication using the adverse events rating scale at every study visit.
Within Trial Assessment Procedure:
The table below indicates the clinical ratings scheduled planned for the trial. Subjects will be evaluated 
every week during the course of the trial. Clinical ratings of symptom severity will be performed by a 
research investigator. A study physician will review laboratory values, assess medication side effects and 
assess study medication compliance.
Study Week
Ope n Exte nsion
Measure
Scre e ning Base line
1
2
4
6
8
10
12
Every 4 Weeks
Yale Global Tic Severity Scale
X
X
X
X
X
X
X
X
X
X
Premonitory Urge Scale
X
X
X
X
X
X
X
X
X
X
Tic Severity
Tourette Syndrome Severity List
X
X
X
X
X
X
X
X
X
X
Yale-Brown Obsessive-Compulsive Scale
X
X
X
X
X
X
X
X
X
Connors ADHD Rating Scale
X
X
X
X
X
X
X
X
Hamilton Depression Scale
X
X
X
X
X
X
X
X
Hamilton Anxiety Scale
X
X
X
X
X
X
X
X
Severity of 
Common 
Comorbid 
Disorders
Clinician-Rated Global Improvement
X
X
X
X
X
X
X
X
X
SCID
X
Psychiatric Medication History
X
Psychiatric 
Assesment
Mental Status Exam
X
Medical History
X
Current Medication List
X
X
Physical Exam
X
X
X
X
X
X
12 Lead ECG
X
X
X
X
X
X
X
X
X
Medical 
Assesment
Vital Signs
X
X
X
X
X
X
X
X
X
Adverse Events Rating Scale
X
X
X
X
X
X
X
X
X
Urine Toxicology
X
X
X
X
X
X
X
X
X
Urine Pregnancy
X
Electrolytes
X
X
X
X
X
X
X
X
LFTs
X
X
X
X
X
X
X
X
PT/PTT
X
X
X
X
X
X
X
X
Safety
BUN/Cr
X
X
X
X
X
X
X
X
Compliance
Pill Counts
X
X
X
X
X
Assignment to THC/PEA combination for 12 weeks. Subjects will receive 
2.3mgTHC/ 518mg PEA for 3 days then 5mg THC/ 518mg PEA 3 days and 
then 10mg THC/518mg PEA for the remainder of the 10 week trial.
10mg THC/518mg 
PEA for an 
additional 24
Weeks.
Extension Phase:
Subjects who report an improvement in the initial 12-week trial will be allowed to continue on the study 
medication (Dronabinol/PEA combination) free of charge for 6 months as long as they continue to complete 
clinical assessments every 4 weeks and test positive for cannabis on urine toxicology screen (indicating
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compliance with study medication). They will be compensated $25 for each follow-up assessment at the 
conclusion of their participation in the trial.
Feasibility
James Leckman and the Yale Child Study Center have nearly a three-decade history of successfully 
recruiting for pharmacological studies of Tourette syndrome.(37-39) We have recently completed a 10- 
subject, uncontrolled trial of EPI-743, in the treatment of adults with Tourette syndrome. We also had been 
recruiting successfully for a placebo-controlled crossover trial of a Fatty acid amide hydrolase (FAAH)- 
inhibitor before it was placed on hold due to clinical concerns with these medications as a class 
(NCT02134080). The inclusion/exclusion criteria are extremely similar between the two trials and thus 
we suspect a large proportion of the subjects completing the EPI-743 and FAAH-inhibitor studies to be 
eligible to enroll in the current trial. Based on this large number of prevalent, research-interested patients 
we expect to meet recruitment goals for the current trial.
4. Genetic Testing   N/A
A. Describe
i.
the types of future research to be conducted using the materials, specifying if 
immortalization of cell lines, whole exome or genome sequencing, genome wide 
association studies, or animal studies are planned
ii. the plan for the collection of material or the conditions under which material will 
be received
iii. the types of information about the donor/individual contributors that will be 
entered into a database
iv. the methods to uphold confidentiality
B. What are the conditions or procedures for sharing of materials and/or distributing for 
future research projects?
C. Is widespread sharing of materials planned?
D. When and under what conditions will materials be stripped of all identifiers?
E. Can donor-subjects withdraw their materials at any time, and/or withdraw the identifiers 
that connect them to their materials?
i.
How will requests to withdraw materials be handled (e.g., material no longer 
identified: that is, anonymized) or material destroyed)?
F. Describe the provisions for protection of participant privacy
G. Describe the methods for the security of storage and sharing of materials
5. Subject Population: Provide a detailed description of the types of human subjects who will 
be recruited into this study.
The subject population will include adults with significant tic symptoms that have not previously 
responded to evidence-based treatments for TS. Subjects will include interested patients from the 
TS/OCD clinic, as well as eligible subjects who respond to the clinicaltrials.gov website posting. 
Additionally, subjects will be recruited via email blast through local TS chapters and by contacting 
local providers who treat adults with TS. Furthermore, contact will be made with adult subjects 
who have recently completed other treatment trials for TS at the clinic and agreed to be contacted 
for future trials.
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6. Subject classification: Check off all classifications of subjects that will be specifically 
recruited for enrollment in the research project. Will subjects who may require additional 
safeguards or other considerations be enrolled in the study? If so, identify the population of 
subjects requiring special safeguards and provide a justification for their involvement.
Children
Healthy
Fetal material, placenta, or dead fetus 
Non-English Speaking
Prisoners
Economically disadvantaged persons 
Decisionally Impaired
Employees
Pregnant women and/or fetuses
Yale Students
Females of childbearing potential
NOTE: Is this research proposal designed to enroll children who are wards of the state as 
potential subjects?
Yes
No (If yes, see Instructions section VII #4 for further 
requirements)
7. Inclusion/Exclusion Criteria: What are the criteria used to determine subject inclusion or 
exclusion?
Inclusion Criteria:

Adult between 18-60 years of age

Meet DSM-5 criteria for the diagnosis of Tourette syndrome

Significant current tic symptoms: YGTSS total tic score greater than or equal to 22 at baseline

On stable psychiatric medication regimen for a minimum of 4 weeks prior to beginning the trial

Accepted method of birth control
Exclusion Criteria:

Comorbid bipolar disorder, psychotic disorder, substance use disorder, developmental disorder or 
intellectual disability (IQ<70)

Recent change (less than 4 weeks) in other medications that have potential effects on tic severity 
(such as alpha-2 agonists (guanfacine, clonidine or prazosin), SSRIs, clomipramine, naltrexone, 
lithium, anxiolytics, topiramate, baclofen etc.). Medication change is defined to include dose 
changes or medication discontinuation.

Recent change in behavioral treatment for Tourette syndrome or comorbid conditions (i.e. OCD) 
within the last 4 weeks or initiation of behavioral therapy for tics within the last 12 weeks.

Taking any co-medications (over the counter or prescription), food supplements/additives which 
can have a drug interaction with dronabinol or PEA.

Positive pregnancy test or drug screening test

History of cannabis dependence

Significant Medical Comorbidity

History of hypersensitivity to any cannabinoid or sesame oil
8. How will eligibility be determined, and by whom?
Subjects will first undergo a phone screen to initially determine eligibility. Information collected 
during the phone screen will be used only in the event that the subject continues to participate in 
the study.
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After determining initial eligibility, research staff will provide a brief description of the research 
and the subject will undergo the screening procedures described previously. Once all screening 
procedures have commenced, research staff, along with the principal investigator, will review all 
relevant information and determine, based on the inclusion and exclusion criteria, if the subject is 
eligible to complete the remaining study procedures.
9. Risks: Describe the reasonably foreseeable risks, including risks to subject privacy, 
discomforts, or inconveniences associated with subjects participating in the research.
A medical assessment including vital signs, ECG, physical exam, routine blood tests indicating physical 
health and urine drug screen and pregnancy test will be completed prior to study enrollment. These safety 
assessments will be repeated every 2 weeks throughout the trial. Additionally, subjects will be assessed 
for any adverse effects of medication using the adverse events rating scale at every study visit.
The risks associated with the study include those related to: 1) screening, 2) phlebotomy, 3)
Dronabinol and 4) confidentiality.
**Note** In previous trials involving PEA, no adverse events have been reported that have 
exceeded the rate observed with placebo controls. The absence of serious side effects or drug- 
drug interactions have been recorded is most likely due to the fact that PEA is an endogenous 
modulator in various foods such as eggs and milk.
1) Screening
All subjects will undergo a Structured Clinical Interview for DSM-IV conducted by a 
research assistant, as well as a psychiatric evaluation by the principal investigator or one of 
the co-investigators. The diagnostic interviews may cover issues which are stressful to a 
person, for example, questions regarding the experience of paranoid thoughts or social 
isolation.
2) Phlebotomy
A medical assessment including vital signs, ECG, physical exam, routine blood tests 
indicating physical health and urine drug screen and pregnancy test will be completed prior 
to study enrollment.  Bruising, infection and thrombosis are all possible consequences of 
phlebotomy.  The medical assessments will occur every two weeks during the 12-week 
trial.  A total of approximately 3 tbsp of blood will be drawn over this time period, an 
amount which is well within the Red Cross blood standards.
3) Dronabinol (synthetic 9THC)
In various studies investigating 9THC in the treatment of patients with AIDS and/or 
cancer, 9THC has been co-administered with a variety of mediations (e.g., cytotoxic 
agents, anti-infective agents, sedatives, or opioid analgesics) without resulting in any 
clinically significant drug/drug interactions.  However, it is possible 9THC may interact 
with other mediations through metabolic and/or pharmacodynamics mechanisms.
Additionally, potential added central nervous system depression may occur if 9THC is 
used in combination with alcohol or other CNS depressants.  Dronabinol is abusable and 
controlled [Schedule III (CIII)] under the Controlled Substance Act. Psychological and
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physiological dependence have been noted in healthy individuals receiving 9THC, 
however addiction is uncommon and has only been seen after prolonged high dose 
administration.  In clinical trials with 9THC in patients with AIDS, no abuse, diversion or 
systemic change in personality or social functioning were observed despite the inclusion of 
a substantial number of patients with a past history of drug abuse.  Side-effects associated 
with 9THC include mood changes, dizziness, drowsiness, confusion, trouble 
concentrating, feeling "high," warmth or tingly feeling, an exaggerated sense of well-being, 
anxiety, lightheadedness, headache, red eyes, dry mouth, nausea, vomiting, stomach pain, 
diarrhea, sleep problems (insomnia), clumsiness, lack of coordination, weakness or, 
unsteadiness.  Serious, uncommon side-effects associated with 9-THC include seizure, 
paranoia, disorganized/unusual behavior and tachycardia. Previous studies have shown 
that PEA is effective in the prevention of cannabis (a substance containing 9THC) 
induced neurotoxicity and neuro-psychiatric disorders. Furthermore, the ability of PEA to 
stabilize mucosal mast cells and prevent their degranulation allows one to overcome the 
over-sensitization/irritation that the 9THC alone causes to the respiratory tract. Thus the 
combination of 9THC with PEA may be prove to be more safe and effective than 9THC 
alone. Currently, approval has been granted from the FDA for the use of 9THC in the 
treatment of anorexia associated with weight loss in patients with AIDS, as well as nausea 
and vomiting associated with cancer chemotherapy in patients who have failed to respond 
adequately to conventional antiemetic treatments.
4) Confidentiality
Participating in research may involve a loss of privacy and confidentiality.  However, as 
will be explained below, extensive procedures have been put in place to secure such 
information.
10. Minimizing Risks: Describe the manner in which the above-mentioned risks will be 
minimized.
1) Screening
Subjects will be carefully screened in order to exclude those with any significant medical 
or psychiatric conditions.  The screening process is rigorous, including a SCID, a 
psychiatric and medical evaluation by a psychiatrist, laboratory tests, ECG, etc., designed 
to screen out unsuitable subjects.
2) Phlebotomy
Due to the risks associated with phlebotomy procedures, subjects who have donated 
blood within eight weeks of the present study will be excluded. Subjects will be 
informed that they should not give blood for at least eight weeks prior to the beginning of 
the study or after completing the trial. Additionally, blood will be drawn by trained 
nurses or phlebotomists using standard sterile phlebotomy procedures.
3) 9THC
The FDA in 1986 granted approval for the use of synthetic 9THC in the treatment of 
anorexia associated with weight loss in patients with AIDS, as well as nausea and 
vomiting associated with cancer chemotherapy in patients who have failed to respond 
adequately to conventional antiemetic treatments. 9-THC is also an active ingredient in 
nabiximols (Sativex patient leaflet), a specific extract of Cannabis, that has been 
approved in the UK for the alleviation of neuropathic pain, spasticity, overactive bladder,
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and other symptoms in multiple sclerosis patients. Furthermore, 9-THC has been 
investigated in a number of clinical trials evaluating its pain reducing effects in various 
patient populations including multiple sclerosis (23), amyotrophic lateral sclerosis (ALS) 
(24), fibromyalgia (25), cancer, abdominal hysterectomy (26), headaches (27), spinal 
cord injury, and muscle spasticity, as well as its symptom reducing effects in obstructive 
sleep apnea (28), internal pressure in end-stage open-angle glaucoma (29, 30), dementia- 
related neuropsychiatric symptoms (NPS), progressive inflammatory brain disease, 
antiemetic effect, colonic motility and sensation.  The risks and benefits of 9THC and 
the specific study procedures will be explained to all participants. After a thorough 
background of 9THC has been provided, subjects will undergo careful physical, 
psychiatric and laboratory examinations to assure the clinical appropriateness and safety 
of their participation in the study.  Close clinical monitoring will ensure the 
appropriateness and safety of subjects’ continued participation. As stated previously, the 
combination of 9THC with PEA may prove to be more safe and effective than 9THC 
alone.
A subject may withdraw consent and stop the clinical trial at any time.  Subjects may be 
discontinued on the study medication if they develop serious adverse symptoms that are 
known side effects of dronabinol including cardiac issues (tachycardia >100bpm or 
hypotension <100/65), physical symptoms (urinary retention, nausea, vomiting, 
abdominal pain) or psychiatric symptoms (psychotic symptoms or anxiety) that does not 
resolve with a decrease in dosage of the study medication. The principal investigator of 
the trial may also withdraw a subject from the trial at any time if he believes the study 
medication poses a significant health risk to the participant.
4) Confidentiality
All subject information will be kept as confidential as possible. Only members of the 
investigative research team with appropriate IRB/HIC and HIPPA training will have 
access to identifying patient information and study data.  Data will be maintained and 
secured in locked file cabinets, on a password protected computer or on an encrypted 
flash drive, all within a locked room.  A numbering coder will be used to assign a unique 
identifier to each subject.  The code number will not be based on any information that 
could be used to identify subjects (for example, social security number, initials, birth 
date, etc.)  As part of the study procedures, some information about subject participation 
in this study will become part of their Connecticut Mental Health Center (CMHC) 
medical record.  If a subject does not already have a medical record at CMHC, one will 
be made for their visit.  Furthermore, if a subject has been a patient at YNHH at any time, 
his or her previous medical records of other visits or admissions will become available to 
the researchers and to the staff of CMHC when the information collected for this research 
is added into their medical record.  Information will be stored as per HIPPA guidelines.
Information will not be dispensed to anyone outside of this research project without prior 
written authorization from the subject.  If it is brought to the attention of the researchers 
that a child is being abused or neglected, or that there is a risk of harm to the subject or 
others, this information will be reported to the appropriate authorities. Records will be 
maintained according to FDA Good Clinical Practice guidelines to ensure protection of 
confidentiality and security of the records.  If requested, participants will be provided
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with a letter explaining the possibility of a positive drug test for cannabis, to their 
employer.
11. Data and Safety Monitoring Plan: Include an appropriate Data and Safety Monitoring Plan 
(DSMP) based on the investigator’s risk assessment stated below. (Note: the HIC will make 
the final determination of the risk to subjects.) For more information, see the Instructions, 
page 24.
a.
What is the investigator’s assessment of the overall risk level for subjects
participating in this study?
The investigator has assessed the overall risk level for subjects participating in the 
study to be moderate.
b. If children are involved, what is the investigator’s assessment of the overall risk 
level for the children participating in this study?
N/A
c.
Include an appropriate Data and Safety Monitoring Plan. Examples of DSMPs are 
available here http://www.yale.edu/hrpp/forms-templates/biomedical.html for
i. Minimal risk
ii. Greater than minimal
Moderate Risk DSMP
1. Personnel responsible for the safety review and its frequency:
The principal investigator will be responsible for monitoring the data, assuring protocol compliance, and 
conducting the safety reviews at the specified frequency of a minimum of every 6 months (including when 
reapproval of the protocol is sought). During the review process, the principal investigator will evaluate 
whether the study should continue unchanged, require modification/amendment, or close to enrollment. 
The principal investigator, the IRB and the Human Investigation Committee (HIC) all have the authority to 
stop or suspend the study or require modifications.
2. The risks associated with the current study are deemed moderate for the following reasons:
(choose those that apply)
1. We do not view the risks associated with the Dronabinol or PEA as minimal.
2. Given the now established safety and validity of the current use of Dronabinol and PEA, we do 
not view the proposed studies as high risk.
Although the proposed study has been assessed as one of moderate risk, the potential exists for anticipated 
and/or unanticipated adverse events, serious or otherwise, to occur since it is not possible to predict with 
certainty the absolute risk in any given individual or in advance of first-hand experience with the proposed 
study methods. Therefore, we provide a plan for monitoring the data and safety of the proposed study as 
follows:
I.
Attribution of Adverse Events:
Adverse events will be monitored for each subject participating in the study and attributed to the study 
procedures/design by the principal investigator (Michael H. Bloch) according to the following 
categories:
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a.) Definite: Adverse event is clearly related to investigational procedures(s)/agent(s). b.) Probable: 
Adverse event is likely related to investigational procedures(s)/agent(s). c.) Possible: Adverse event 
may be related to investigational procedures(s)/agent(s). d.) Unlikely: Adverse event is likely not to be 
related to the investigational procedures(s)/agent(s). e.) Unrelated: Adverse event is clearly not related 
to investigational procedures(s)/agent(s).
II.
Plan for Grading Adverse Events:
The following scale will be used in grading the severity of adverse events noted during the study:
1. Mild adverse event
2. Moderate adverse event
3. Severe
III.
Plan for Determining Seriousness of Adverse Events: Serious Adverse Events:
In addition to grading the adverse event, the principal investigator will determine whether the adverse 
event meets the criteria for a Serious Adverse Event (SAE). An adverse event is considered serious if 
it:
1. is life-threatening OR
2. results in in-patient hospitalization or prolongation of existing hospitalization OR
3. results in persistent or significant disability or incapacity OR
4. results in a congenital anomaly or birth defect OR
5. results in death OR
6. based upon appropriate medical judgment, may jeopardize the subject’s health and may require 
medical or surgical intervention to prevent one of the other outcomes listed in this definition, OR
7. adversely affects the risk/benefit ratio of the study
An adverse event may be graded as severe but still not meet the criteria for a Serious Adverse Event. 
Similarly, an adverse event may be graded as moderate but still meet the criteria for an SAE. It is 
important for the PI to consider the grade of the event as well as its “seriousness” when determining 
whether reporting to the IRB is necessary.
IV.
Plan for reporting Reportable Adverse Events and other unanticipated problems involving 
risks to subjects or others to the IRB
The principal investigator will report the following types of events to the IRB: a) adverse events that 
are serious or life-threatening AND unanticipated (or anticipated but occurring with a greater frequency 
than expected) AND possibly, probably or definitely related to the drug/device/intervention; and b) 
other unanticipated problems involving risks to subjects or others.
These adverse events or unanticipated problems involving risks to subjects or others will be reported 
to the IRB in accordance with IRB Policy 710, using the appropriate forms found on the website.
V.
Plan for reporting adverse events to co-investigators on the study, as appropriate the 
protocol’s research monitor(s), e.g., industrial sponsor, Yale Cancer Center Data and Safety 
Monitoring Committee (DSMC), Protocol Review Committee (PRC), DSMBs, study 
sponsors, funding and regulatory agencies, and regulatory and decision-making bodies.
For the current study, the following individuals, funding, and/or regulatory agencies will be notified 
(choose those that apply):

All Co-Investigators listed on the protocol

Yale Cancer Center Data and Safety Monitoring Committee (DSMC)

National Institutes of Health

Food and Drug Administration (Physician-Sponsored IND #131864 )
The principal investigator (Michael H. Bloch) will conduct a review of all adverse events upon completion 
of every study subject. The principal investigator will evaluate the frequency and severity of the adverse 
events and determine if modifications to the protocol or consent form are required.
d. For multi-site studies for which the Yale PI serves as the lead investigator: N/A
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i. How will adverse events and unanticipated problems involving risks to subjects or 
others be reported, reviewed and managed?
ii. What provisions are in place for management of interim results?
iii. What will the multi-site process be for protocol modifications?
12. Statistical Considerations: Describe the statistical analyses that support the study design.
Go/No-Go Decision for Larger Multi-Site Phase III Trial
The important go/no-go decision is whether the trial, which is not a true efficacy trial but rather a Phase II 
pilot, provides sufficient encouragement to move forward for a Phase III trial. We propose a series of 
benchmarks for feasibility, tolerability and preliminary efficacy in an initial trial for go/no-go decision- 
making. Feasibility: Average treatment compliance with the Dronabinol/PEA combination of at least 80% 
(via pill counts and positive urine drug screen) during the trial. Tolerability: Attrition due to AEs of 4 or 
fewer subjects receiving treatment. Safety: Four or fewer subjects have a greater than 20% worsening of 
tic symptoms while in the trial. Efficacy: An average improvement of YGTSS severity of greater than 10% 
during the course of the 12-week trial.
Assuming all go/no-go decision points are met in the trial, we will additionally use the initial pilot data to 
design the most appropriate phase III trial design. Specifically, we will examine difference in tic severity 
as assessed by YGTSS (across all subjects and specifically those assigned to active medication) between 
week 0 (baseline) and week 12 (endpoint) to determine the time at which treatment benefits likely plateau.
SECTION VI: RESEARCH INVOLVING DRUGS, BIOLOGICS, RADIOTRACERS, PLACEBOS AND
DEVICES
If this section (or one of its parts, A or B) is not applicable, state N/A and delete the rest of the 
section.
A. DRUGS, BIOLOGICS and RADIOTRACERS
1. Identification of Drug, Biologic or Radiotracer: What is (are) the name(s) of the drug(s) 
biologic(s) or radiotracer(s) being used? Identify whether FDA approval has been granted and for what 
indication(s).
In addition to PEA, other names of the drug include: Palmitoylethanolamide, C18H37NO2, PeaPure, 
Normast, Impulsin, MimyX, N-(2-hydroxyethyl)palmitate and N-palmitoylethanolamine. FDA 
approval has not been granted for the use of PEA.  However, PEA is a primary fatty acid amine found 
in egg yolk.  Therefore, it falls under the definition of egg yolk-derived phospholipids, which are listed 
on the FDA list of “Generally Recognized as Safe” with a designated number GRN No. 411. Content 
of PEA can also be seen under the FDA List of Indirect Additives Used in Food Contact Substances 
under general main term: ANIMAL OIL FATTY ACID AMIDES, Doc No. 7625, CAS RN 977139- 
08-4.
Other names for 9THC include: 9-Tetrahydracannabinol, Dronabinol, Marinol and C21H30O2.  Currently, 
approval has been granted from the FDA for the use of 9THC in the treatment of anorexia associated with 
weight loss in patients with AIDS, as well as nausea and vomiting associated with cancer chemotherapy in 
patients who have failed to respond adequately to conventional antiemetic treatments.
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All protocols which utilize a drug, biologic or radiotracer not approved by, but regulated by, the FDA, 
or a radiotracer regulated by the RDRC, must provide the following information:
a. What is the Investigational New Drug (IND) number assigned by the FDA? 131864
b. Who holds the IND? Michael H. Bloch MD, MS
c. All protocols which utilize a radiotracer not approved by, but regulated by the FDA must 
provide the IND number:
N/A 
Alternatively, use of the investigational radiotracer may be under RDRC/RSC oversight: (check 
if appropriate)    N/A 
For all investigational radiotracers, attach a copy of the RDRC/RSC application (for 
radioisotopes used in the PET Center, PET Center personnel may complete this step)
Go to http://rsc.med.yale.edu/login.asp?url=myApps.asp.  When you have logged in, complete 
the application and attach a copy to this submission.
Alternatively, an exemption from IND filing requirements may be sought for a clinical 
investigation of a drug product that is lawfully marketed in the United States. If there is no IND and 
an exemption is being sought, review the following categories and complete the category that applies 
(and delete the inapplicable categories):
Exempt Category 1
The clinical investigation of a drug product that is lawfully marketed in the United States can be 
exempt from IND regulations if all of the following are yes:
i. The intention of the investigation is NOT to report to the FDA as a well-controlled study in support 
of a new indication for use or to be used to support any other significant change in the labeling for 
the drug.
Yes
No
ii. The drug that is undergoing investigation is lawfully marketed as a prescription drug product, and 
the intention of the investigation is NOT to support a significant change in the advertising for the 
product.
Yes
No
iii. The investigation does NOT involve a route of administration or dosage level or use in populations 
or other factor that significantly increases the risks (or decreases the acceptability of the risks) 
associated with the use of the drug product.
Yes
No
iv. The investigation will be conducted in compliance with the requirements for institutional (HIC) 
review and with the requirements for informed consent of the FDA regulations (21 CFR Part 50 
and 21 CFR Part 56).      Yes       No
v. The investigation will be conducted in compliance with the requirements regarding promotion and 
charging for investigational drugs.
Yes
No
Exempt Category 2 (all items i, ii, and iii must be checked to grant a category 2 exemption)
i. The clinical investigation is for an in vitro diagnostic biological product that involves one or 
more of the following (check all that apply):
Blood grouping serum 
Reagent red blood cells 
Anti-human globulin
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ii. The diagnostic test is intended to be used in a diagnostic procedure that confirms the 
diagnosis made by another, medically established, diagnostic product or procedure; and
iii. The diagnostic test is shipped in compliance with 21 CFR §312.160.
Exempt Category 3
The drug is intended solely for tests in vitro or in laboratory research animals if shipped in 
accordance with 21 CFR 312.60
Exempt Category 4
A clinical investigation involving use of a placebo if the investigation does not otherwise 
require submission of an IND.
2. Background Information: Provide a description of previous human use, known risks, and data 
addressing dosage(s), interval(s), route(s) of administration, and any other factors that might 
influence risks. If this is the first time this drug is being administered to humans, include relevant 
data on animal models.
See pages 9-12 under “Background” for this information.
3. Source: a) Identify the source of the drug or biologic to be used. 
Therapix Biosciences Ltd.
b) Is the drug provided free of charge to subjects?
Yes
No 
If yes, by whom?
Therapix Biosciences Ltd.
4. Storage, Preparation and Use: Describe the method of storage, preparation, stability information, 
and for parenteral products, method of sterilization and method of testing sterility and 
pyrogenicity.
Dronabinol will be stored in a well-closed container and in a cool environment between 8° and 
15°C (46° and 59°F) such as a refrigerator, as these are the storage recommendations from the 
FDA. Additionally, arrangements will be made with the CMHC investigational pharmacy 
regarding proper storage, preparation and stability information for both Dronabinol and PEA.
Check applicable Investigational Drug Service utilized:
YNHH IDS
Yale Cancer Center
CMHC Pharmacy
West Haven VA
PET Center
None
Other:
Note: If the YNHH IDS (or comparable service at CMHC or WHVA) will not be utilized, explain in 
detail how the PI will oversee these aspects of drug accountability, storage, and preparation.
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5. Use of Placebo:
Not applicable to this research project
If use of a placebo is planned, provide a justification which addresses the following:
a.
Describe the safety and efficacy of other available therapies. If there are no other 
available therapies, state this.
The following therapies are currently available for the treatment of TS: 1) Neuroleptic 
medications, 2) atypical neuroleptics, 3) α2-receptors agonists and 4) habit reversal training 
(HRT).
b. State the maximum total length of time a participant may receive placebo while on the study.
c.
Address the greatest potential harm that may come to a participant as a result of receiving 
placebo.
d. Describe the procedures that are in place to safeguard participants receiving placebo.
6. Use of Controlled Substances:
Will this research project involve the use of controlled substances in human subjects?
Yes
No  See HIC Application Instructions to view controlled substance listings.
If yes, is the use of the controlled substance considered:
Therapeutic: The use of the controlled substance, within the context of the research, has the 
potential to benefit the research participant.
Non-Therapeutic: Note, the use of a controlled substance in a non-therapeutic research study 
involving human subjects may require that the investigator obtain a Laboratory Research License. 
Examples include controlled substances used for basic imaging, observation or biochemical 
studies or other non-therapeutic purposes. See Instructions for further information.
7. Continuation of Drug Therapy After Study Closure
Not applicable to this project
Are subjects provided the opportunity to continue to receive the study drug(s) after the study has 
ended?
Yes   If yes, describe the conditions under which continued access to study drug(s) may apply 
as well as conditions for termination of such access.
Subjects who report an improvement in the initial 12-week trial will be allowed to continue on 
the study medication (Dronabinol/PEA combination) free of charge for 6 months as long as they 
continue to complete clinical assessments every 4 weeks and test positive for cannabis on urine 
toxicology screen (indicating compliance with study medication).  They will be compensated
$25 for each follow-up assessment at the conclusion of their participation in the trial.
No
If no, explain why this is acceptable.
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B. DEVICES 
N/A
1.
Are there any investigational devices used or investigational procedures performed at Yale- 
New Haven Hospital (YNHH) (e.g., in the YNHH Operating Room or YNHH Heart and 
Vascular Center)?  ☐Yes   ☒No
If Yes, please be aware of the following requirements:
a.
A YNHH New Product/Trial Request Form must be completed via EPIC: Pull down the 
Tools tab in the EPIC Banner, Click on Lawson, Click on “Add new” under the New 
Technology Request Summary and fill out the forms requested including the “Initial 
Request Form,” “Clinical Evidence Summary, “ and attach any other pertinent 
documents. Then select “save and submit” to submit your request; and
b. Your request must be reviewed and approved in writing by the appropriate YNHH 
committee before patients/subjects may be scheduled to receive the investigational device 
or investigational procedure.
2. What is the name of the device to be studied in this protocol? 
Has this device been FDA approved?
Yes
No
If yes, state for what indication.
3. Background Information: Provide a description of previous human use, known risks, and 
any other factors that might influence risks. If this is the first time this device is being used in 
humans, include relevant data on animal models.
4. Source:
a) Identify the source of the device to be used.
b) Is the device provided free of charge to subjects?
Yes
No
5.  What is the PI’s assessment of risk level (significant or non-significant) associated with the 
use of the device?
Significant Risk (SR) Device Study: A study of a device that presents a potential for serious 
risk to the health, safety, or welfare of a participant and 1) is intended as an implant; 2) is used in 
supporting or sustaining human life; or otherwise prevents impairment of human health; 3) is of 
substantial importance in diagnosing, curing, mitigating or treating disease, or otherwise prevents
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impairment of human health; or 4) otherwise presents a potential for serious risk to the health, 
safety, or welfare of a participant.
Significant Risk Devices require an Investigational Device Exemption (IDE) issued by the FDA. 
What is the IDE number assigned by the FDA?
Did the FDA approve this IDE as Category A (experimental/investigational) or as Category B
(non-experimental/investigational)? 
Who holds the IDE?
Non-Significant Risk (NSR) Device Study: A study of a device that does not meet the 
definition for a significant risk device and does not present a potential for serious risk to the health, 
safety, or welfare of participants.  Note that if the HIC concurs with this determination, an IDE is 
not required.
6.
Abbreviated IDE or Exempt IDE: There are abbreviated requirements for an IDE and 
there also are exemptions to the requirement for an IDE. See the criteria in the HIC 
Application Instructions, Section VI.B.4 at  
http://www.yale.edu/hrpp/resources/docs/100FR1aHICProtocol_Application_Instructions5-   
25-11.pdf to determine if these pertain to this study.
Abbreviated IDE or Exempt IDE – If criteria set forth in the HIC Application Instructions 
are met, copy and paste the completed relevant section from the Instructions into this application.
7.
Investigational device accountability:
a.
State how the PI, or named designee, ensures that an investigational device is used only in 
accordance with the research protocol approved by the HIC, and maintains control of the 
investigational device as follows:
Maintains appropriate records, including receipt of shipment, inventory at the 
site, dispensation or use by each participant, and final disposition and/or the return of the 
investigational device (or other disposal if applicable):
Documents pertinent information assigned to the investigational device (e.g., date, quantity, batch 
or serial number, expiration date if applicable, and unique code number):
Stores the investigational device according to the manufacturer's recommendations with respect to 
temperature, humidity, lighting, and other environmental considerations:
Ensures that the device is stored in a secure area with limited access in accordance with applicable 
regulatory requirements:
Distributes the investigational device to subjects enrolled in the IRB-approved protocol:
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SECTION VII: RECRUITMENT/CONSENT AND ASSENT PROCEDURES
1. Targeted Enrollment: Give the number of subjects:
a.
targeted for enrollment at Yale for this protocol_18_
b.
If this is a multi-site study, give the total number of subjects targeted across all
sites
N/A_
2. Indicate recruitment methods below.  Attach copies of any recruitment materials that will be used.
Flyers
Internet/Web Postings
Radio
Posters
Mass E-mail Solicitation
Telephone
Letter
Departmental/Center Website
Television
Medical Record Review
Departmental/Center Newsletters
Departmental/Center Research Boards
Web-Based Clinical Trial Registries
Newspaper
YCCI Recruitment database
Clinicaltrials.gov Registry (do not send materials to HIC)
Other (describe):
3.
Recruitment Procedures:
a.
Describe how potential subjects will be identified.
Subjects will be recruited through the TS/OCD Clinic at the Yale Child Study Center. Additionally, 
subjects will be contacted through email blast through local TS chapters and by contacting local 
providers who treat adults with TS. Furthermore, adult subjects that have recently completed other 
treatment trials for TS at the clinic and agreed to be contacted for future trials will be recruited. Study 
information, along with the contact phone number, will be posted on clinicaltrials.gov. The YCCI 
recruitment database and flyers will also be used.
b. Describe how potential subjects are contacted.
Research staff will contact adult subjects who have recently completed other treatment trials for TS 
at the clinic and agreed to be contacted for future studies. All other potential subjects will be asked 
to contact the research staff through the advertisement methods listed previously.
c.
Who is recruiting potential subjects?
The clinicians at the Yale TS/OCD (PI and/or co-investigators), as well as the study 
personnel, members of Dr. Bloch’s research team.
4. Screening Procedures
a.
Will email or telephone correspondence be used to screen potential subjects for 
eligibility prior to the potential subject coming to the research office?
Yes
No
b.
If yes, identify below all health information to be collected as part of screening and 
check off any of the following HIPAA identifiers to be collected and retained by the 
research team during this screening process.
HEALTH INFORMATION TO BE COLLECTED:
A brief psychiatric and medical history will be collected during telephone screening including Axis I 
diagnoses, medical and neurologic diagnoses, as well as recent medication and psychotherapy
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changes. All information will be stored in locked cabinets/password protected computer in an office 
that is locked. Information that will breach subject confidentiality will not be shared. Rather, data will 
only be released upon written consent of the subject and will be available for review by the Yale 
human Investigation Committee. We will hold paper files for seven years at which point they will be 
destroyed.
HIPAA identifiers:
Names
All geographic subdivisions smaller than a State, including: street address, city, county, precinct, zip codes and their 
equivalent geocodes, except for the initial three digits of a zip code if, according to the current publicly-available data from 
the Bureau of the Census: (1) the geographic unit formed by combining all zip codes with the same three initial digits contains 
more than 20,000 people, and (2) the initial three digits of a zip code for all such geographic units containing 20,000 or fewer 
people is changed to 000.
Telephone numbers 
Fax numbers
E-mail addresses
Social Security numbers 
Medical record numbers
Health plan beneficiary numbers 
Account numbers
All elements of dates (except year) for dates related to an individual, including: birth date, admission date, discharge 
date, date of death, all ages over 89 and all elements of dates (including year) indicative of such age, except that such ages 
and elements may be aggregated into a single category of age 90 or older
Certificate/license numbers
Vehicle identifiers and serial numbers, including license plate numbers 
Device identifiers and serial numbers
Web Universal Resource Locators (URLs) 
Internet Protocol (IP) address numbers
Biometric identifiers, including finger and voice prints  
Full face photographic images and any comparable images
Any other unique identifying numbers, characteristics, or codes
5. Assessment of Current Health Provider Relationship for HIPAA Consideration:
Does the Investigator or any member of the research team have a direct existing clinical 
relationship with any potential subject?
Yes, all subjects
Yes, some of the subjects 
No
If yes, describe the nature of this relationship.
Subjects who have been seen in the clinic may be recruited. Some subjects may be referred for 
psychopharmacology consult. Other subjects may come specifically because of interest in the study. No subjects 
will be taken off current medication or withdrawn from ongoing therapy in order to participate in the trial,  
unless the current medication is ineffective or causes unacceptable adverse effects. Patients who are not 
interested in the study will be treated in the usual clinical manner.
6. Request for waiver of HIPAA authorization: (When requesting a waiver of HIPAA Authorization 
for either the entire study, or for recruitment purposes only. Note: if you are collecting PHI as part of 
a phone or email screen, you must request a HIPAA waiver for recruitment purposes.)
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Choose one:
□For entire study
☒ For recruitment purposes only
□For inclusion of non-English speaking subject if short form is being used
i. Describe why it would be impracticable to obtain the subject’s authorization for 
use/disclosure of this data;
A waiver of HIPAA authorized is being requested for recruitment purposes only. 
Subjects will be initially recruited through word of mouth, TS advocacy organizations, 
physician referrals and internet ads.  PHI such as name, telephone number and email 
addresses will be needed to schedule initial screening interviews.  It would be 
impractical to coordinate initial subject enrollment and recruitment without this data.
ii. If requesting a waiver of signed authorization, describe why it would be 
impracticable to obtain the subject’s signed authorization for use/disclosure of this 
data;
Signed authorization is impractical, as the initial screening patients recruited through 
advertisements or referral may occur via phone or email.
By signing this protocol application, the investigator assures that the protected 
health information for which a Waiver of Authorization has been requested will not 
be reused or disclosed to any person or entity other than those listed in this 
application, except as required by law, for authorized oversight of this research 
study, or as specifically approved for use in another study by an IRB.
Researchers are reminded that unauthorized disclosures of PHI to individuals outside of the Yale 
HIPAA-Covered entity must be accounted for in the “accounting for disclosures log”, by subject 
name, purpose, date, recipients, and a description of information provided.  Logs are to be 
forwarded to the Deputy HIPAA Privacy Officer.
7. Required HIPAA Authorization: If the research involves the creation, use or disclosure of 
protected health information (PHI), separate subject authorization is required under the 
HIPAA Privacy Rule. Indicate which of the following forms are being provided:
Compound Consent and Authorization form 
HIPAA Research Authorization Form
8. Consent Personnel: List the names of all members of the research team who will be obtaining 
consent/assent.
Michael H. Bloch, MD, MS, James F. Leckman, MD, Angeli Landeros-Weisenberger, MD, and 
Jessica A. Johnson, BS.
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9. Process of Consent/Assent: Describe the setting and conditions under which consent/assent will 
be obtained, including parental permission or surrogate permission and the steps taken to ensure 
subjects’ independent decision-making.
Investigators and/or research staff will obtain consent during the initial screening visit.  During 
this visit, all aspects of the study will be discussed and the inclusion criteria will be explained.
10. Evaluation of Subject(s) Capacity to Provide Informed Consent/Assent: Indicate how the 
personnel obtaining consent will assess the potential subject’s ability and capacity to consent to the 
research being proposed.
The consent documents will be reviewed verbally with the subject.  If for any reason, it becomes 
clear that the subject cannot comprehend trial design or procedures, they will not be enrolled in 
the study.
11. Documentation of Consent/Assent: Specify the documents that will be used during the 
consent/assent process. Copies of all documents should be appended to the protocol, in the same 
format that they will be given to subjects.
Compound Authorization Form
12. Non-English Speaking Subjects: Explain provisions in place to ensure comprehension for 
research involving non-English speaking subjects. If enrollment of these subjects is anticipated, 
translated copies of all consent materials must be submitted for approval prior to use.
This protocol will not involve non-English speaking subjects.
12(a) As a limited alternative to the above requirement, will you use the short form* for 
consenting process if you unexpectedly encounter a non-English speaking individual interested 
in study participation and the translation of the long form is not possible prior to intended 
enrollment?
YES ☐ NO ☐
Note* If more than 2 study participants are enrolled using a short form translated into the same 
language, then the full consent form should be translated into that language for use the next time 
a subject speaking that language is to be enrolled.
Several translated short form templates are found on our website
at: http://www.yale.edu/hrpp/forms-templates/biomedical.html. If the translation of the short 
form is not available on our website, then the translated short form needs to be submitted to the 
IRB office for approval via amendment prior to enrolling the subject. Please review the 
guidance and presentation on use of the short form available on the HRPP website.
If using a short form without a translated HIPAA Research Authorization Form, please 
request a HIPAA waiver in the section above.
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13. Consent Waiver: In certain circumstances, the HIC may grant a waiver of signed consent, or 
a full waiver of consent, depending on the study. If you will request either a waiver of consent, 
or a waiver of signed consent for this study, complete the appropriate section below.
Not Requesting a consent waiver 
Requesting a waiver of signed consent 
Requesting a full waiver of consent
A. Waiver of signed consent: (Verbal consent from subjects will be obtained. If PHI is 
collected, information in this section must match Section VII, Question 6)
Requesting a waiver of signed consent for Recruitment/Screening only
If requesting a waiver of signed consent, please address the following:
a. Would the signed consent form be the only record linking the subject and the research?
Yes
No
b. Does a breach of confidentiality constitute the principal risk to subjects? 
Yes
No
OR
c. Does the research activity pose greater than minimal risk?
Yes If you answered yes, stop. A waiver cannot be granted. Please note: 
Recruitment/screening is generally a minimal risk research activity
No
AND
d. Does the research include any activities that would require signed consent in a non- 
research context?
Yes
No
Requesting a waiver of signed consent for the Entire Study (Note that an information 
sheet may be required.)
If requesting a waiver of signed consent, please address the following:
a. Would the signed consent form be the only record linking the subject and the research?
Yes
No
b. Does a breach of confidentiality constitute the principal risk to subjects? 
Yes
No
OR
c. Does the research pose greater than minimal risk?
Yes If you answered yes, stop. A 
waiver cannot be granted.
No
AND
d. Does the research include any activities that would require signed consent in a non- 
research context?
Yes
No
B. Full waiver of consent: (No consent from subjects will be obtained for the activity.)
Requesting a waiver of consent for Recruitment/Screening only
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a. Does the research activity pose greater than minimal risk to subjects?
Yes If you answered yes, stop. A waiver cannot be granted. Please note: 
Recruitment/screening is generally a minimal risk research activity
No
b. Will the waiver adversely affect subjects’ rights and welfare?
Yes
No
c. Why would the research be impracticable to conduct without the waiver?
d. Where appropriate, how will pertinent information be returned to, or shared with 
subjects at a later date?
Requesting a full waiver of consent for the Entire Study (Note: If PHI is 
collected, information here must match Section VII, question 6.)
If requesting a full waiver of consent, please address the following:
a. Does the research pose greater than minimal risk to subjects? 
Yes If you answered yes, stop. A waiver cannot be granted.
No
b. Will the waiver adversely affect subjects’ rights and welfare?
Yes
No
c. Why would the research be impracticable to conduct without the waiver?
d. Where appropriate, how will pertinent information be returned to, or shared with 
subjects at a later date?
SECTION VIII: PROTECTION OF RESEARCH SUBJECTS
Confidentiality & Security of Data:
a.
What protected health information (medical information along with the HIPAA identifiers) 
about subjects will be collected and used for the research?
Research staff will collect and use for research the following private identifiable 
information from subjects after consent is obtained: name, age, address, telephone number, 
email address, diagnosis, results from the clinical evaluation, clinical rating scales, 
laboratory tests (blood and urine), electrocardiogram (ECG) and physical examination 
results. Scientific reports will be written in aggregate terms. Individual responses will not 
be described if the data is published.
b. How will the research data be collected, recorded and stored?
Clinical data, outcomes of diagnostic instruments and research data will be collected by 
the principal investigator, co-investigators and study personnel. Collected information will 
be stored in a locked file cabinet in a locked office. Data will be entered by study personnel 
into a database, using a secured server, on a password protected computer in a locked 
office. Data may also be stored on an encrypted flash drive that will be stored in a locked 
office.
c.
How will the digital data be stored?
CD
DVD
Flash Drive
Portable Hard
Drive
Secured Server
Laptop Computer
Desktop Computer
Other
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d.
What methods and procedures will be used to safeguard the confidentiality and security of 
the identifiable study data and the storage media indicated above during and after the subject’s 
participation in the study?
Do all portable devices contain encryption software?
Yes
No
If no, see http://hipaa.yale.edu/guidance/policy.html
All data will be coded and stored in locked cabinets on a password protected computer, as 
well as an encrypted flash drive, in a locked office. Private identifiable information about 
individuals will not be shared. A numbering code will be used to assign a unique identifier 
to each subject, that of which will be used for data entry stored on all secure electronic 
devices. Information that will breach subject confidentiality will only be released upon 
written consent of the subject and will be available for review by the Yale Human 
Investigation Committee. A Certificate of Confidentiality has been  obtained.
e.
What will be done with the data when the research is completed? Are there plans to destroy 
the identifiable data? If yes, describe how, by whom and when identifiers will be destroyed. If 
no, describe how the data and/or identifiers will be secured.
Paper files will be held for seven years after the completion of the study. After that point, 
all paper files will be destroyed. As noted previously, archived computer files will not 
have any identifying patient information.
f. Who will have access to the protected health information (such as the research sponsor, the 
investigator, the research staff, all research monitors, FDA, Yale Cancer Center Data and Safety 
Monitoring Committee (DSMC), SSC, etc.)? (please distinguish between PHI and de-identified 
data)
The principal investigator, co-investigators and all study personnel.
g. If appropriate, has a Certificate of Confidentiality been obtained?
h.
YES Are any of the study procedures likely to yield information subject to mandatory 
reporting requirements? (e.g. HIV testing – reporting of communicable diseases; parent interview 
-incidents of child abuse, elderly abuse, etc.). Please verify to whom such instances will need to 
be reported.
Yes.  Evidence of abuse or situations in which the subject is deemed a danger to self or 
others will be reported.
SECTION IX: POTENTIAL BENEFITS
Potential Benefits: Identify any benefits that may be reasonably expected to result from the 
research, either to the subject(s) or to society at large. (Payment of subjects is not considered a 
benefit in this context of the risk benefit assessment.)
Subjects may benefit from the medical and psychiatric evaluations that they will receive while 
participating in the study.  Patients will receive a higher level of evaluation and care than routine 
treatment.
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SECTION X: RESEARCH ALTERNATIVES AND ECONOMIC CONSIDERATIONS
1.
Alternatives: What other alternatives are available to the study subjects outside of the research?
Subjects may continue any current mediations or therapy, those of which might include various 
antipsychotics or alpha-2 antagonists, as well as habit reversal therapy.  All of these interventions 
have demonstrated efficacy for the treatment of TS. Subjects will be presented with the risks and 
benefits of each of the treatments.  Additionally, subjects will be offered any of the previously 
stated treatments that they have not received prior to enrolling in the trial.
2.
Payments for Participation (Economic Considerations): Describe any payments that will be 
made to subjects, the amount and schedule of payments, and the conditions for receiving this 
compensation.
Participants may be paid up to $650 total as compensation for participating in this study. They will 
receive a stipend payment of $80 for the in-person screening assessment, $70 for the Baseline, 
Week 4, Week 8, and Week 12 assessments; and $35 for the Week 1, Week 2, Week 6 and Week 
10 assessments. Additionally, They will receive a stipend payment of $25 for each clinical follow- 
up assessment that you complete. Follow-up assessments will take place every 4 weeks for 6 
months, after the end of the initial 12-week trial. Participants will receive such payments only for 
those visits that are completed.
If the participant travels more than 50 miles each way in order to participate in the study, they also 
may receive reimbursement for reasonable lodging and travel expenses in addition to the stipend 
outlined above, up to a total of $200.00 per visit. Participants will need to provide receipts of your 
costs to the study coordinator.
According to the rules of the Internal Revenue Service (IRS), payments that are made to research 
subjects as a result of their participation in a study may be considered taxable income.
3.
Costs for Participation (Economic Considerations): Clearly describe the subject’s costs 
associated with participation in the research, and the interventions or procedures of the study that 
will be provided at no cost to subjects.
Subjects will not be charged for the study medications, clinical assessments, services or laboratory 
tests directly related to the study. As previously noted, some subjects may be seen for a clinical 
consultation at the Yale Child Study Center TS/OCD Clinic piror to study entry. Clinical 
consultation will be charged as part of care in the usual manner.
4.
In Case of Injury: This section is required for any research involving more than minimal risk.
a.
Will medical treatment be available if research-related injury occurs?
Yes
b. Where and from whom may treatment be obtained?
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Initial assessment and appropriate referral will be carried out by the research team. The PI 
(Michael H. Bloch, MD, MS) will conduct an assessment to determine whether the events 
were considered “related to the study treatment” or not. The research team will participate 
in assessment and appropriate disposition of the case. Disposition has taken many forms: 
assumed ongoing clinical care of the subject, securing of appropriate referrals and 
discontinued involvement in the patient’s care, as well as a combined approach in which 
care is provided in collaboration with appropriate specialists. In all cases, the disposition 
is guided by the family’s preference and clinical judgment regarding the subject’s best 
interest. Every reasonable effort will be made to incorporate the interest of the subject’s 
primary care provider.
c.
Are there any limits to the treatment being provided?
The  intervention  will  focus  on  assessment  and  securing  an  appropriate  referral  in 
collaboration with the family and the primary care provider.
d. Who will pay for this treatment?
Assessment and referral services will be provided without charge.  Ongoing care will be 
paid for by the family or the family’s insurance carrier.
e.
How will the medical treatment be accessed by subjects?
As previously noted, the occurrence of an adverse event requiring care outside of the 
confines of the study will initially be assessed by the research time. Referral’s to the 
family’s primary care provider or other specialists will be made in accordance with the 
nature of the subject’s problem.
**Note** In order to simply and clarify these points in the consent form, the following 
statement was added to the compound authorization form:
“If you are injured during your participation in this study, treatment will be provided, but you or your 
insurance company will be responsible for the cost of this treatment. There are no provisions for financial 
compensation for injuries. You do not give up any of your legal rights by signing this form.”
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REFERENCES
1.
Scahill L, Sukhodolsky DG, Williams SK, Leckman JF. Public health significance of tic 
disorders in children and adolescents. Adv Neurol. 2005;96:240-8.
2.
Bloch MH, Peterson BS, Scahill L, Otka J, Katsovich L, Zhang H, et al. Adulthood 
outcome of tic and obsessive-compulsive symptom severity in children with Tourette 
syndrome. Arch Pediatr Adolesc Med. 2006;160(1):65-9.
3.
Cheung MY, Shahed J, Jankovic J. Malignant Tourette syndrome. Mov Disord. 
2007;22(12):1743-50.
4.
Roessner V, Plessen KJ, Rothenberger A, Ludolph AG, Rizzo R, Skov L, et al. European 
clinical guidelines for Tourette syndrome and other tic disorders. Part II: pharmacological 
treatment. Eur Child Adolesc Psychiatry. 2011;20(4):173-96.
5.
Scahill L, Erenberg G, Berlin CM, Jr., Budman C, Coffey BJ, Jankovic J, et al. 
Contemporary assessment and pharmacotherapy of Tourette syndrome. NeuroRx. 
2006;3(2):192-206.
6.
Pringsheim T, Doja A, Gorman D, McKinlay D, Day L, Billinghurst L, et al. Canadian 
guidelines for the evidence-based treatment of tic disorders: pharmacotherapy. Can J 
Psychiatry. 2012;57(3):133-43.
7.
Sandyk R, Awerbuch G. Marijuana and Tourette's syndrome. J Clin 
Psychopharmacol. 1988;8(6):444-5.
8.
Hemming M, Yellowlees PM. Effective treatment of Tourette's syndrome with 
marijuana. J Psychopharmacol. 1993;7(4):389-91.
9.
Muller-Vahl KR, Schneider U, Kolbe H, Emrich HM. Treatment of Tourette's 
syndrome with delta-9-tetrahydrocannabinol. Am J Psychiatry. 1999;156(3):495.
10.
Muller-Vahl KR, Kolbe H, Schneider U, Emrich HM. Cannabinoids: possible role in 
patho-physiology and therapy of Gilles de la Tourette syndrome. Acta Psychiatr Scand. 
1998;98(6):502-6.
11.
Muller-Vahl KR, Schneider U, Koblenz A, Jobges M, Kolbe H, Daldrup T, et al. 
Treatment of Tourette's syndrome with Delta 9-tetrahydrocannabinol (THC): a randomized 
crossover trial. Pharmacopsychiatry. 2002;35(2):57-61.
12.
Muller-Vahl KR, Schneider U, Prevedel H, Theloe K, Kolbe H, Daldrup T, et al. Delta 9- 
tetrahydrocannabinol (THC) is effective in the treatment of tics in Tourette syndrome: a 6- 
week randomized trial. J Clin Psychiatry. 2003;64(4):459-65.
13.
Morera-Herreras T, Miguelez C, Aristieta A, Ruiz-Ortega JA, Ugedo L. 
Endocannabinoid modulation of dopaminergic motor circuits. Front Pharmacol. 
2012;3:110.
14.
Fernandez-Ruiz J. The endocannabinoid system as a target for the treatment of 
motor dysfunction. Br J Pharmacol. 2009;156(7):1029-40.
15.
Hohmann AG, Herkenham M. Localization of cannabinoid CB(1) receptor mRNA in 
neuronal subpopulations of rat striatum: a double-label in situ hybridization study. 
Synapse. 2000;37(1):71-80.
16.
Kataoka Y, Kalanithi PS, Grantz H, Schwartz ML, Saper C, Leckman JF, et al. 
Decreased number of parvalbumin and cholinergic interneurons in the striatum of 
individuals with Tourette syndrome. J Comp Neurol. 2010;518(3):277-91.
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Page 39 of 161
17.
Vasileiou I, Fotopoulou G, Matzourani M, Patsouris E, Theocharis S. Evidence for the 
involvement of cannabinoid receptors' polymorphisms in the pathophysiology of human 
diseases. Expert opinion on therapeutic targets. 2013;17(4):363-77.
18.
Rahn EJ, Hohmann AG. Cannabinoids as pharmacotherapies for neuropathic pain: 
from the bench to the bedside. Neurotherapeutics : the journal of the American Society for 
Experimental NeuroTherapeutics. 2009;6(4):713-37.
19.
Haney M, Hart CL, Vosburg SK, Comer SD, Reed SC, Foltin RW. Effects of THC and 
lofexidine in a human laboratory model of marijuana withdrawal and relapse. 
Psychopharmacology.    2008;197(1):157-68.
20.
Iskedjian M, Bereza B, Gordon A, Piwko C, Einarson TR. Meta-analysis of cannabis 
based treatments for neuropathic and multiple sclerosis-related pain. Current medical 
research and opinion. 2007;23(1):17-24.
21.
Whiting PF, Wolff RF, Deshpande S, Di Nisio M, Duffy S, Hernandez AV, et al. 
Cannabinoids for Medical Use: A Systematic Review and Meta-analysis. Jama. 
2015;313(24):2456-73.
22.
Martin-Sanchez E, Furukawa TA, Taylor J, Martin JL. Systematic review and meta- 
analysis of cannabis treatment for chronic pain. Pain medicine. 2009;10(8):1353-68.
23.
Svendsen KB, Jensen TS, Bach FW. Does the cannabinoid dronabinol reduce central 
pain in multiple sclerosis? Randomised double blind placebo controlled crossover trial. 
Bmj. 2004;329(7460):253.
24.
Weber M, Goldman B, Truniger S. Tetrahydrocannabinol (THC) for cramps in 
amyotrophic lateral sclerosis: a randomised, double-blind crossover trial. Journal of 
neurology, neurosurgery, and psychiatry. 2010;81(10):1135-40.
25.
Weber J, Schley M, Casutt M, Gerber H, Schuepfer G, Rukwied R, et al. 
Tetrahydrocannabinol (Delta 9-THC) Treatment in Chronic Central Neuropathic Pain and 
Fibromyalgia Patients: Results of a Multicenter Survey. Anesthesiology research and 
practice. 2009;2009.
26.
Buggy DJ, Toogood L, Maric S, Sharpe P, Lambert DG, Rowbotham DJ. Lack of 
analgesic efficacy of oral delta-9-tetrahydrocannabinol in postoperative pain. Pain. 
2003;106(1-2):169-72.
27.
Napchan U, Buse DC, Loder EW. The use of marijuana or synthetic cannabinoids for 
the treatment of headache. Headache. 2011;51(3):502-5.
28.
Prasad B, Radulovacki MG, Carley DW. Proof of concept trial of dronabinol in 
obstructive sleep apnea. Frontiers in psychiatry. 2013;4:1.
29.
Flach AJ. Delta-9-tetrahydrocannabinol (THC) in the treatment of end-stage open- 
angle glaucoma. Transactions of the American Ophthalmological Society. 2002;100:215-22; 
discussion 22-4.
30.
Tomida I, Azuara-Blanco A, House H, Flint M, Pertwee RG, Robson PJ. Effect of 
sublingual application of cannabinoids on intraocular pressure: a pilot study. Journal of 
glaucoma. 2006;15(5):349-53.
31.
Leussink VI, Husseini L, Warnke C, Broussalis E, Hartung HP, Kieseier BC. 
Symptomatic therapy in multiple sclerosis: the role of cannabinoids in treating spasticity. 
Therapeutic advances in neurological disorders. 2012;5(5):255-66.
32.
Kahlich R, Klima J, Cihla F, Frankova V, Masek K, Rosicky M, et al. Studies on 
prophylactic efficacy of N-2-hydroxyethyl palmitamide (Impulsin) in acute respiratory
APPROVED BY THE YALE UNIVERSITY IRB 9/27/2017 VALID THROUGH 10/25/2018


APPROVED BY THE YALE UNIVERSITY IRB 9/27/2017 VALID THROUGH 10/25/2018
Page 40 of 161
infections. Serologically controlled field trials. Journal of hygiene, epidemiology, 
microbiology, and immunology. 1979;23(1):11-24.
33.
Masek K, Perlik F, Klima J, Kahlich R. Prophylactic efficacy of N-2-hydroxyethyl 
palmitamide (impulsin) in acute respiratory tract infections. European journal of clinical 
pharmacology. 1974;7(6):415-9.
34.
Plesnik V, Havrlantova M, Jancova J, Januska J, Mackova O. [Impulsin in the 
prevention of acute respiratory diseases in school children]. Ceskoslovenska pediatrie. 
1977;32(6):365-9.
35.
Wiedermannova D, Lokaj J, Wiedermann D. [Prophylactic administration of impulsin 
to clinically healthy children. The effect on T and B lymphocytes in peripheral blood 
(author's transl)]. Casopis lekaru ceskych. 1979;118(40-41):1249-51.
36.
Wiedermannova D, Wiedermann D, Lokaj J. [Prophylactic administration of impulsin 
to clinically healthy children.--effect on the serum proteins and metabolic activity of 
granulocytes (author's transl)]. Casopis lekaru ceskych. 1978;117(33):1030-4.
37.
Leckman JF, Hardin MT, Riddle MA, Stevenson J, Ort SI, Cohen DJ. Clonidine 
treatment of Gilles de la Tourette's syndrome. Arch Gen Psychiatry. 1991;48(4):324-8.
38.
Scahill L, Chappell PB, Kim YS, Schultz RT, Katsovich L, Shepherd E, et al. A placebo- 
controlled study of guanfacine in the treatment of children with tic disorders and attention 
deficit hyperactivity disorder. Am J Psychiatry. 2001;158(7):1067-74.
39.
Scahill L, Leckman JF, Schultz RT, Katsovich L, Peterson BS. A placebo-controlled 
trial of risperidone in Tourette syndrome. Neurology. 2003;60(7):1130-5.
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APPENDIXES:
Appendix 1: Previous Trials of Δ9-tetrahydracannabinol
Primary Medical 
Condition
Number of
Administered Drug
Main Results
Reference
Patients
Central neuropathic pain in 
patients
with multiple sclerosis
24 
patients 
aged 
between 23 and 55 
years
Orally
administered dronabinol 
at a maximum dose of
10 
mg 
daily 
or 
corresponding placebo f 
or three weeks (15-21 
days), separated by a 
three 
week 
washout 
period.
Median     spontaneous pain intensity     was     significantly     lower 
during dronabinol treatment than during placebotreatment (4.0 (25th to 
75th centiles 2.3 to 6.0) v 5.0 (4.0 to 6.4), P = 0.02), and median pain relief
score (numerical rating scale) was higher (3.0 (0 to 6.7) v> 0 (0 to 2.3), P
= 0.035). The functional ability of the multiple sclerosis patients did not 
change.
Svendsen, K. B., Jensen, T. S., and 
Bach, F. W. (2004). Does the 
cannabinoid 
dronabinol 
reduce 
central pain in multiple sclerosis? 
Randomised double blind placebo 
controlled crossover trial. BMJ. 
329: 253-260
Central neuropathic pain in 
patients
with multiple sclerosis
339 patients
Sativex
Interim analysis at week 10 showed a statistically significant treatment 
difference in favor of THC/CBD spray at this time point (p = 0.046). 
During the randomized-withdrawal phase, the primary endpoint of time to 
treatment failure was statistically significant in favor of THC/CBD spray, 
with 57 % of patients receiving placebo failing treatment versus 24 % of 
patients from the THC/CBD spray group (p = 0.04).
Langford RM, Mares J, Novotna 
A,
et
al. 
A 
double-blind, 
randomized, 
placebo-controlled,
parallel-group study of THC/CBD 
oromucosal
spray
in combination with the existing 
treatment
regimen, in the relief of central 
neuropathic
pain
in 
patients with multiple sclerosis. J 
Neurol.
2013;260
(4):984-997


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Central neuropathic pain in 
patients
with multiple sclerosis
Cannabis
based
medicinal
extracts 
(CBME)
Young CA, Rog DJ. (2003) 
Randomised     controlled     trial 
of 
cannabis 
based 
medicinal 
extracts 
(CBME) 
in 
central 
neuropathic pain due to multiple 
sclerosis. Paper presented at: IV 
Congress 
of 
the 
European 
Federation 
of 
IASP 
Chapters 
(EFIC); September 2-6, 2003; 
Prague, Czech Republic.
Multiple    sclerosis-induced 
neuropathic pain
15
relapsing- 
remitting
MS 
patients with MS- 
induced NPP
Nabilone or placebo was 
titrated over 4 weeks 
(0.5 mg/week increase) 
followed 
by 
5-week 
maintenance 
of 1 mg 
oral nabilone (placebo) 
twice daily in patients 
stabilized on GBP
Significant group × time(2) interaction term was reported for both the VAS 
pain (P < 0.01) and VASimpact score (P < 0.01), demonstrating the 
adjusted rate of decrease for both outcomes was statistically greater in 
nabilone vs placebo study group.
Turcotte D, Doupe M, Torabi M, 
Gomori A, Ethans K, Esfahani F, 
Galloway K, Namaka M (2015) 
Nabilone as an adjunctive to 
gabapentin for multiple sclerosis- 
induced 
neuropathic 
pain: 
a 
randomized controlled trial. Pain 
Med. 2015 Jan;16(1):149-59


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Page 43 of 161
Central   pain   in   multiple 
sclerosis (MS)
66 patients with MS 
and 
central 
pain 
states
(59
dysesthetic, 
seven 
painful spasms)
Whole-plant 
cannabis- 
based medicine (CBM), 
containing 
delta-9- 
tetrahydrocannabinol:ca 
nnabidiol 
(THC:CBD) 
delivered 
via 
an 
oromucosal spray, 
as 
adjunctive 
analgesic 
treatment (Each spray 
delivered 2.7 mg of THC 
and 2.5 of CBD, and 
patients could gradually 
self-titrate 
to 
 
a 
maximum of 48 sprays 
in 24 hours.)
CBM was superior to placebo in reducing the mean intensity of pain (CBM 
mean change -2.7, 95% CI: -3.4 to -2.0, placebo -1.4 95% CI: -2.0 to -0.8, 
comparison between groups, p = 0.005) and sleep disturbance (CBM mean 
change -2.5, 95% CI: -3.4 to -1.7, placebo -0.8, 95% CI: -1.5 to -0.1,
comparison between groups, p = 0.003).
Rog, D. J., Nurmikko, T. J., Friede, 
T., and Young, C. A. (2005). 
Randomized, controlled trial of 
cannabis-based medicine in central 
pain 
in 
multiple 
sclerosis. 
Neurology. 65: 812-819.
Central   pain   in   multiple 
sclerosis (MS)
24 MS patients
Dronabinol
Dronabinol reduced the spontaneous pain intensity significantly compared 
with placebo (4.0 (2.3-6.0) vs. 5.0 (4.0-6.4), median (25th-75th 
percentiles), p = 0.02).
Svendsen KB, Jensen TS, Bach 
FW. (2005) [Effect of the synthetic 
cannabinoid dronabinol on central 
pain in patients with multiple 
sclerosis–secondary publication]. 
Ugeskr Laeger. 167(25-31):2772-
2774


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Page 44 of 161
Central 
neuropathic 
pain 
from 
brachial 
plexus 
avulsion
48 patients
THC 
25 
mg/ml 
or 
THC:CBD 25 mg/ml 
given 
as 
 
patient 
activated 
oromucosal 
100ul sprays or placebo
Pain VAS was 6.1 for THC and THC:CBD compared to 6.7 for placebo, 
11-point box scale was 43.6 for THC and 45.1 for THC:CBD, compared 
to 52.9 for placebo.
Berman J, Lee J, Cooper M, et al. 
(2003) Efficacy of two cannabis- 
based medicinal extracts for relief 
of central neuropathic pain from 
brachial plexus avulsion: results of 
a randomised controlled trial. 
Paper presented at: Pain Society 
Annual Meeting; April 1-4, 2003; 
Glasgow, 
United 
Kingdom. 
Anaesthesia. 2003;58(9):938
Chronic pain associated with 
brachial plexus root avulsion
48 patients with at 
least one avulsed 
root and baseline 
pain score of four or 
more on an 11-point 
ordinate scale
Placebo and two whole 
plant
extracts
of 
Cannabis sativa L.: GW- 
1000-02
(Sativex), 
containing 
Delta(9)tetrahydrocanna 
binol (THC):cannabidiol 
(CBD)
in
an 
approximate   1:1   ratio 
and
GW-2000-02,
containing
primarily 
THC
The primary outcome measure (mean pain severity score during the last 7 
days of treatment) failed to fall by the two points defined in our hypothesis. 
However, both this measure and measures of sleep showed statistically 
significant improvements. The study medications were generally well 
tolerated with the majority of adverse events, including intoxication type 
reactions, being mild to moderate in severity and resolving spontaneously.
Berman, J. S., Symonds, C., and 
Birch, R. (2004). Efficacy of two 
cannabis based medicinal extracts 
for relief of central neuropathic 
pain 
from 
brachial 
plexus 
avulsion: results of a randomised 
controlled  trial.  Pain.  112:  299-
306.


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Page 45 of 161
Neuropathic pain
Mild 
dose 
cannabis 
3.53% THC by weight, 
Low 
dose 
cannabis 
1.29% THC by weight, 
Placebo
cannabis 
placebo marijuana.
The primary outcome variable, VAS Pain Intensity, was assessed by 
asking participants to indicate the intensity of their current pain on a 100- 
mm visual analog scale (VAS) between 0 (no pain) and 100 (worst possible 
pain).An assessment was performed before the administration of vaporized 
cannabis or placebo and hourly thereafter for six hours.
University of California Davis. 
Center for Medicinal Cannabis 
Research, VA Northern California 
Health Care System. Effects of 
vaporized 
marijuana 
on 
neuropathic
pain.
ClinicalTrials.gov. 
http://ClinicalTrials.gov/show/NC 
T01037088.   Accessed   April   7, 
2014
Neuropathic pain
High 
dose 
cannabis 
(7.5% THC by weight), 
Low 
dose 
cannabis 
(3.5% THC by weight), 
and Placebo cannabis
Score on a series of pain scales (heat pain threshold, VAS intensity, VAS 
unpleasantness, pain relief, neuropathic pain scale) was assessed
Center  for  Medicinal  Cannabis 
Research.    Effects    of    smoked 
marijuana  on  neuropathic  pain. 
ClinicalTrials.gov. 
http://ClinicalTrials.gov/show/NC 
T00254761.   Accessed   April   7, 
2014
Neuropathic pain
38    patients    with 
central
and 
peripheral 
neuropathic pain
High-dose (7%), low- 
dose (3.5%), or placebo 
cannabis
A mixed linear model demonstrated an analgesic response to smoking 
cannabis. No effect on evoked pain was seen. Psychoactive effects were 
minimal and well-tolerated, with some acute cognitive effects, particularly 
with memory, at higher doses.
Wilsey, 
B., 
Marcotte, 
T., 
Tsodikov, A., Millman, J. and 
others. (2008). A randomized, 
placebo-controlled, crossover trial 
of 
cannabis 
cigarettes 
in 
neuropathic pain. J.Pain. 9: 506-
521


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Page 46 of 161
Pain of neurological origin
70
GW-1000-02 vs placebo
Change From Baseline in Mean Pain Box Scale-11 Score at 3 Weeks was
-1.3 (1.67) for GW-1000-02 and -0.9 (1.62) for placebo, while Use of 
Analgesic Escape Medication was 20.57 (33.08) for GW-1000-02, 
comparing to 50.12  (44.10) for placebo
GWPharmaceuticals Ltd. A study 
to
evaluate
the   effects   of   cannabis   based 
medicine
in
patients 
with pain of neurological origin. 
ClinicalTrials.gov. 
http://ClinicalTrials.gov/show/NC 
T01606176
Accessed April 7, 2014
Chronic pain
1 56-year-old man 
who 
developed 
chronic
pain
following
the 
excision of a facial 
cancer
Nabilone
Condition was poorly controlled despite multiple analgesic medications. 
Following the starting of nabilone (a synthetic cannabinoid) his pain 
control was greatly improved and this had a huge impact on his quality of 
life.
Reynolds TD, Osborn HL (2013) 
The use of cannabinoids in chronic 
pain. BMJ Case Rep. 2013 Jul 26;
Chronic pain
30 patients taking 
opioids for chronic 
pain
Dronabinol
(Marinol 
capsules;
Solvay 
Pharmaceuticals, 
Brussels,  Belgium)  10 
mg or 20 mg
Patients who received dronabinol experienced decreased pain intensity and 
increased satisfaction compared with placebo. No differences in benefit 
were found between the 20 mg and 10 mg doses.
Narang, S., Gibson, D., Wasan, A. 
D., Ross, E. L. and others. (2008). 
Efficacy of dronabinol as an 
adjuvant treatment for  chronic 
pain patients on opioid therapy. 
J.Pain. 9: 254-264


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Page 47 of 161
Chronic pain
30 patients
Nabilone
(1/4)-1 
mg/day)
Throughout the cross-over periods the nabilone treatment was superior 
(medians [25%-; 75%-percentiles]: nabilone/placebo): decrease of the 
average spinal pain intensity within the last 4 weeks (DeltaVAS) 0.9 [0.0; 
2.0]  /  0.5  [0.0;  1.7],  decrease  of  the  current  spinal  pain  intensity
(DeltaVAS) 0.6 [0.0; 2.5] / 0.0 [-1.0, 1.0] (p = .006), decrease of the 
average headache intensity within the last 4 weeks (DeltaVAS) 1.0 [-1.0; 
2.4] / 0.2 [-0.9; 1.0], increase of the number of days without headache
within the last 4 weeks 2.0 [0.0; 6.5] / 0.0 [-5.0; 4.0], increase of the quality
of life (DeltaQOL-Score) 5.0 [0.8; 10.8] / 2.0 [-2.3; 8.0].
Pinsger M, SchimettaW, Volc D, 
Hiermann E, Riederer F, PolzW. 
(2006) [Benefits of an add-on 
treatment 
with 
the 
synthetic 
cannabinomimetic nabilone 
on 
patients with chronic pain—a 
randomized controlled trial]. Wien 
KlinWochenschr. 118(11-12):327-
335
Chronic pain
30
Dronabinol (Marinol) as 
Add-On 
Therapy 
for 
Patients on Opioids
Brigham andWomen’s Hospital; 
Solvay Pharmaceuticals. Study to 
evaluate the efficacy of dronabinol 
(Marinol) as add on therapy for 
patients on opioids for chronic 
pain.
ClinicalTrials.gov. 
http://ClinicalTrials.gov/show/NC 
T00153192.
Accessed 
April 7, 2014


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Page 48 of 161
Chronic back pain
(synthetic 
cannabinomimeticum)
Pinsger M. (2012) Benefit of an 
add-on-treatment with a synthetic 
cannabinomimeticum on patients 
with 
chronic 
back 
pain-a 
randomized controlled trial. Paper 
presented at 8th International 
Conference on Early Psychosis: 
From Neurobiology to Public 
Policy; October 11-13, 2012; San 
Francisco: CA. Eur Spine J. 
21(11):2366
Chronic Central Neuropathic 
Pain and Fibromyalgia
124
7.5 mg delta 9-THC over 
7 months
Psychometric parameters (PDI, SF-12, QLIP, HADS) and pain intensity 
improved significantly during delta 9-THC treatment. Opioid doses were 
reduced and patients perceived THC therapy as effective with tolerable 
side effects. About 25% of the patients, however, did not tolerate the 
treatment.
Weber, J., Schley, M., Casutt, M., 
Gerber, H. and others. (2009). 
Tetrahydrocannabinol (Delta 9- 
THC) 
Treatment 
in 
Chronic 
Central Neuropathic Pain and 
Fibromyalgia Patients: Results of a 
Multicenter
Survey. 
Anesthesiol.Res.Pract.          2009:
827290.-
Chronic neuropathic pain
100
Nabilone
and 
dihydrocodeine
Mean pain score as measured by VAS 0 - 10 for the last two weeks on 
treatment
Cambridge Laboratories Ltd. A 
randomised, 
crossover, 
double 
blind comparison of the analgesic 
effect and patient tolerability of 
Nabilone and dihydrocodeine in 
chronic 
neuropathic 
pain. 
metaRegister of Controlled Trials. 
http://isrctn.org/ISRCTN1533075
7. Accessed April 7, 2014


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Page 49 of 161
Chronic neuropathic pain
21 patients
Ajulemic acid (AJA)  or 
placebo capsules
The results showed no significant reduction in mechanical hypersensitivity 
(p=0.052), although a tendency towards pain reduction could be seen. The 
VAS score showed significant pain reduction (p=0.021) and NNT values 
for 30% pain relief were 2.14 for the first treatment group and 5.29 for the 
second treatment group. No significant findings were observed regarding 
psychotropic or physical measurements.
Salim K, Schneider U, Burstein S, 
Hoy L, Karst M. (2005) Pain 
measurements and side effect 
profile of the novel cannabinoid 
ajulemic
acid.
Neuropharmacology   48(8):1164-
71
Chronic neuropathic pain
21 
patients 
(8 
women and 13 men) 
aged 29 to 65 years 
(mean, 51 years)
1',1'dimethylheptyl- 
Delta8- 
tetrahydrocannabinol- 
11-oic  acid  (CT-3),  a 
potent  analog  of  THC- 
11-oic acid (Two daily 
doses of CT-3 (four 10- 
mg capsules per day) or 
identical
placebo 
capsules)
The mean differences over time for the VAS values in the CT-3-placebo 
sequence measured 3 hours after intake of study drug differed significantly 
from those in the placebo-CT-3 sequence (mean [SD], -11.54 [14.16] vs 
9.86 [21.43]; P =.02).
Karst M, Salim K, Burstein S, 
Conrad I, Hoy L, Schneider U. 
(2003) Analgesic effect of the 
synthetic cannabinoid CT-3 on 
chronic 
neuropathic 
pain: 
a 
randomized 
controlled 
trial. 
JAMA. 290(13): 1757-1762


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Page 50 of 161
Chronic neuropathic pain
96 
patients 
with 
chronic neuropathic 
pain, 
aged 
23-84 
years
Maximum daily dose of 
240 mg dihydrocodeine 
or 2 mg nabilone
The mean score was 6.0 mm longer for nabilone than for dihydrocodeine 
(95% confidence interval 1.4 to 10.5) in the available case analysis and 5.6 
mm (10.3 to 0.8) in the per protocol analysis. Dihydrocodeine provided 
better pain relief than nabilone and had slightly fewer side effects.
Frank B, Serpell MG, Hughes J, 
Matthews JNS, Kapur D. (2008) 
Comparison of analgesic effects 
and patient tolerability of nabilone 
and dihydrocodeine for chronic 
neuropathic 
pain: 
randomised, 
crossover, double blind study. 
BMJ. 336 (7637):199-201
Chronic neuropathic pain
Cannabis
containing 
9.43%
THC
versus
cannabis containing 0% 
THC
Montreal General Hospital. Pilot 
study of smoked cannabis for 
chronic 
neuropathic 
pain. 
metaRegister of Controlled Trials 
(mRCT),
http://www.controlledtrials.com/I 
SRCTN68314063 Accessed April 
7, 2014.
Central neuropathic pain
Sativex
Berman J, Bosworth T, Guy G, 
Stott C; Sativex Spinal Cord Injury 
Study Group. Sativex in the 
treatment of central neuropathic 
pain due to spinal cord injury: a 
randomised 
controlled 
study. 
Paper presented at: British Pain 
Society 
Annual 
 
Scientific 
Meeting; April 2007; Glasgow: 
United Kingdom.


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Page 51 of 161
Central neuropathic pain
339
Sativex vs placebo
Change From Baseline in Mean Pain Due to MS NRS Score was -2.02 
(2.15) for Sativex and -1.89 (2.33) for placebo, while Change in Pain From 
Baseline to End of the Treatment Using the NPS (Neuropathic Pain Scale) 
was -14.24 (18.17) for Sativex, comparing to -11.44 (17.86) for placebo.
GWPharmaceuticals Ltd. Sativex 
versus placebo when added to 
existing 
treatment for central 
neuropathic 
pain 
inMS. 
http://ClinicalTrials.gov/show/NC 
T00391079 Accessed April 7, 
2014
Neuropathic    pain    despite 
traditional treatment
39    patients    with 
central
and 
peripheral 
neuropathic pain
Inhaling    medium-dose 
(3.53%),
low-
dose(1.29%), or placebo 
cannabis
There was no significant difference between the 2 active dose groups' 
results (P > .7). The number needed to treat (NNT) to achieve 30% pain 
reduction was 3.2 for placebo versus low-dose, 2.9 for placebo versus 
medium-dose, and 25 for medium- versus low-dose. As these NNTs are 
comparable to those of traditional neuropathic painmedications, cannabis 
has analgesic efficacy with the low dose being as effective a pain reliever 
as the medium dose. Psychoactive effects were minimal and well tolerated, 
and neuropsychological effects were of limited duration and readily 
reversible within 1 to 2 hours.
Wilsey, B., Marcotte, T., Deutsch, 
R., Gouaux, B. and others. (2012). 
Low-Dose Vaporized Cannabis 
Significantly
Improves 
Neuropathic Pain. J.Pain. 14: 136-
148


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Page 52 of 161
Peripheral Neuropathic Pain, 
characterized by Allodynia
80
THC
plac
CBD,
1:1
and 
ebo
GWPharma Ltd. A double blind, 
randomised, placebo controlled 
parallel group study of cannabis 
based medicine extract (CBME), 
in the treatment of peripheral 
neuropathic pain characterised by 
allodynia. 
metaRegister 
of 
Controlled
Trials.
http://www.controlled- 
trials.com/ISRCTN38250575 
Accessed April 7, 2014
Peripheral Neuropathic Pain, 
characterized by Allodynia
Sativex
Ongoing
GWPharma Ltd. A double blind, 
randomised, placebo controlled, 
parallel group study of Sativex, in 
the treatment of subjects with 
peripheral 
neuropathic 
pain 
associated with allodynia. EU 
Clinical 
Trials 
Register. 
https://www.clinicaltrialsregister.e 
u/ctrsearch/search?query=eudract
_number:2004-002531-32. 
Accessed
April
8, 2014.


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Page 53 of 161
Neuropathic
pain 
characterized by allodynia
Sativex
Nurmikko TJ, Serpell  
MG, 
Hoggart B, Toomey PJ, Morlion 
BJ. (2005) A multi-centre, double- 
blind, randomized, controlled trial 
of oro-mucosal cannabis based 
medicine in the treatment of 
neuropathic pain characterized by 
allodynia. 
Neurology. 
64(suppl 
1):A374
Pain and allodynia
125
Oro-mucosal
sativex, 
(THC: CBD)
The mean reduction in pain intensity scores (primary outcome measure) 
was greater in patients receiving sativex than placebo (mean adjusted 
scores -1.48 points vs. -0.52 points on a 0-10 Numerical Rating Scale 
(p=0.004; 95% CI: -1.59, -0.32). Improvements in Neuropathic Pain Scale 
composite score (p=0.007), sleep NRS (p=0.001), dynamic allodynia 
(p=0.042), punctate allodynia (p=0.021), Pain Disability Index (p=0.003) 
and Patient's Global Impression of Change (p<0.001) were similarly 
greater on sativex vs. placebo. Sedative and gastrointestinal side effects 
were reported more commonly by patients on active medication.
Nurmikko, T. J., Serpell, M. G., 
Hoggart, B., Toomey, P. J. and 
others.
(2007).
Sativex 
successfully treats  neuropathic 
pain characterised by allodynia: a 
randomised,
double-blind, 
placebo-controlled clinical trial. 
Pain. 133: 210-220


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Page 54 of 161
Pain   due   to   rheumatoid 
arthritis(RA)
58  patients  over  5 
weeks
CBM
(Sativex)
and 
placebo
In comparison with placebo, the CBM produced statistically significant 
improvements in pain on movement,pain at rest, quality of sleep, DAS28 
and the SF-MPQ pain at present component. There was no effect on 
morning stiffness but baseline scores were low. The large majority of 
adverse effects were mild or moderate.
Blake, D. R., Robson, P., Ho, M., 
Jubb, R. W. and others. (2006). 
Preliminary assessment of the 
efficacy, tolerability and safety of 
a 
cannabis-based 
medicine 
(Sativex) in the treatment of pain 
caused by rheumatoid arthritis. 
Rheumatology. (Oxford). 45: 50-
52.
TMJ
pain
caused
by 
osteoarthritis
24
300mg at morning + 
600mg at evening for 7 
days; 
followed 
by 
300mg/bid for 7 days 
Vs 
ibupfofen  
(600 
mg/tid
for 14 days)
Among the completers, pain relief was greater with cannabis than placebo 
(median difference in DDS pain intensity change, 3.3 points, effect 
size=0.60; p=0.016). The proportions of subjects achieving at least 30% 
pain relief with cannabis versus placebo were 0.46 (95%CI 0.28, 0.65) and 
0.18 (0.03, 0.32).
Ellis, R. J., Toperoff, W., Vaida, 
F., van den Brande, G. and others. 
(2009). 
Smoked 
medicinal 
cannabis
for
neuropathic 
pain 
in 
HIV: 
a 
randomized, 
crossover 
clinical 
trial. Neuropsychopharmacology. 
34: 672-680
Analgesia
Delta(9)-THC 
5 
mg 
orally or placebo and 90 
min later morphine 0.02 
mg/kg intravenously or 
placebo
Among affective responses, although neither morphine nor Delta(9)-THC 
had a significant effect, there was a positiveanalgesic interaction between 
the two (p = 0.012), indicating that the combination had a synergistic 
affective analgesic effect.
Roberts, J. D., Gennings, C., and 
Shih, 
M. 
(2006). 
Synergistic 
affective 
analgesic 
interaction 
between
delta-9-
tetrahydrocannabinol
and 
morphine.  Eur.J.Pharmacol.  530:
54-58.


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Page 55 of 161
Noncancer pain
30
chronic
noncancer         pain
patients 
taking 
opioids 
and 
not 
using marijuana
Placebo,  10  or  20  mg 
dronabinol
The 10 and 20 mg dronabinol doses had significantly elevated scores over 
time on 4/5 subscales versus placebo (P<0.05). Average daily morphine 
use, total pain relief (TOTPAR), age, sex, and baseline pain level were not 
significant covariates. ARCI peak effects at 2 hours were similar to peak 
effects of smoked marijuana at 30 minutes (P=0.80, 10 mg=low strength, 
20 mg=high strength).
Issa MA, Narang S, Jamison RN, 
Michna E, Edwards RR, Penetar 
DM, Wasan AD (2014) The 
subjective psychoactive effects of 
oral dronabinol studied in a 
randomized, controlled crossover 
clinical trial for pain. Clin J Pain. 
30(6):472-8
Chronic noncancer pain
20
Nabilone followed  up 
for an average of 1.5 
years
Fifteen patients reported subjective overall improvement with nabilone, 
and nine reported reduced pain intensity. Beneficial effects on sleep and 
nausea were the main reasons for continuing use. Intolerable side effects 
were experienced in three patients (palpitations, urinary retention, dry 
mouth).
Berlach, D. M., Shir, Y., and 
Ware, M. A. (2006). Experience 
with the synthetic cannabinoid 
nabilone in chronic noncancer 
pain. Pain Med. 7: 25-29
Post-traumatic
or 
postsurgical 
neuropathic 
pain
23, 2 weeks
Cannabis
at
four 
potencies   (0%,   2.5%,
6%
and
9.4% 
tetrahydrocannabinol)
A single inhalation of 25 mg of 9.4% tetrahydrocannabinol herbal cannabis 
three times daily for five days reduced the intensity of pain, improved sleep 
and was well tolerated.
Ware, M. A., Wang, T., Shapiro, 
S., Robinson, A. and others. 
(2010). Smoked 
cannabis 
for 
chronic       neuropathic        pain: 
a randomized controlled trial. 
CMAJ. 182: E694-E701


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Page 56 of 161
Pain tolerance
Marijuana and placebo
A statistically significant increase in tolerance was observed after smoking 
marijuana. Although there was no statistically significant interaction 
between the drug effect and having had previous cannabis experience, 
there was a definite trend towards a greater increase for the experienced 
(16%) compared to the naive group(8%).
Milstein, S. L., MacCannell, K., 
Karr, G., and Clark, S. (1975). 
Marijuana-produced changes in 
pain tolerance. Experienced and 
non-experienced
subjects. 
Int.Pharmacopsychiatry. 10: 177-
182
Antinociception
5
male
regular 
marijuana users
Marijuana
(3.
55% 
Delta(9)- 
tetrahydrocannabinol 
(Delta(9)-THC)
(active))
Marijuana produced significant dose-dependent antinociception (increased 
finger withdrawal latency) and biobehavioral effects. Naltrexone did not 
significantly influence marijuana dose-effect curves, suggesting no role of 
endogenous opiates in marijuana-induced antinociception under these 
conditions.
Greenwald, M. K. and Stitzer, M.
L. 
(2000). 
Antinociceptive, 
subjective and behavioral effects 
of smoked marijuana in humans. 
Drug Alcohol Depend. 59: 261- 
275


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Page 57 of 161
Pain 
and 
hyperalgesia 
induced 
by 
intradermal 
capsaicin
15
healthy
volunteers
Low-, 
medium-, 
and 
high-dose
smoked 
cannabis 
(respectively 
2%, 4%, and 8% 9-delta- 
tetrahydrocannabinol by 
weight)
By 45 min aftercannabis exposure, there was a significant decrease in 
capsaicin-induced pain with the medium dose and a significant increase in 
capsaicin-induced pain with the high dose. There was no effect seen with 
the low dose, nor was there an effect on the area of hyperalgesia at any 
dose. Significant negative correlations between pain perception and 
plasma delta-9-tetrahydrocannabinol levels were found after adjusting for 
the overall dose effects. There was no significant difference in 
performance on the neuropsychological tests.
Wallace, 
M., 
Schulteis, 
G., 
Atkinson, J. H., Wolfson, T. and 
others. (2007). Dose-dependent 
effects of smoked cannabis on 
capsaicin-induced 
pain 
and 
hyperalgesia in healthy volunteers. 
Anesthesiology. 107: 785-796
Capsaicin-induced pain and 
hyperalgesia
30    healthy    male 
volunteers
Single doses of nabilone 
(1, 2 or 3 mg)
Pain and hyperalgesia were measured at baseline and 2-3.5 h after dosing. 
Nabilone did not significantly attenuate either ongoing pain or primary or 
secondary hyperalgesia, whereas dose-dependent CNS effects were 
observed from 1.5 to 6 h after dosing, being maximal at 4-6 h.
Kalliomaki, 
J., 
Philipp, 
A., 
Baxendale, J., Annas, P. and 
others. (2012). Lack of effect of 
central 
nervous 
system-active 
doses of nabilone on capsaicin- 
induced pain and hyperalgesia. 
Clin.Exp.Pharmacol.Physiol.   39:
336-342
Anti-hyperalgesic properties 
upon capsaicin stimulation
Cannabinoid
receptor 
ligand HU210
Pre-treatment with HU210 significantly reduced the perception of pain 
following the administration of capsaicin.
Rukwied, 
R., 
Watkinson, 
A., 
McGlone, F., and Dvorak, M. 
(2003). 
Cannabinoid 
agonists 
attenuate
capsaicin-induced 
responses in human skin. Pain. 
102: 283-288


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Page 58 of 161
Pain
12
healthy
volunteers
THC (20 mg), morphine 
(30 mg), THC-morphine 
(20 mg THC+30 mg 
morphine), or placebo 
were given orally and as 
single doses
THC did not significantly reduce pain. In the cold and heat tests it even 
produced hyperalgesia, which was completely neutralized by THC- 
morphine. A slight additive analgesic effect could be observed for THC- 
morphine in the electrical stimulation test. No analgesic effect resulted in 
the pressure and heat test, neither with THC nor THC-morphine. 
Psychotropic and somatic side-effects (sleepiness, euphoria, anxiety, 
confusion, nausea, dizziness, etc.) were common, but usually mild.
Naef, M., Curatolo, M., Petersen- 
Felix, S., Arendt-Nielsen, L. and 
others. 
(2003). 
The 
analgesic 
effect 
of 
oral 
delta-9- 
tetrahydrocannabinol 
(THC), 
morphine, and a THC-morphine 
combination in healthy subjects 
under 
experimental 
pain 
conditions. Pain. 105: 79-88
Pain due to spinal cord injury 
(SCI)
116
GW-1000-02 (THC (27
mg/ml) and CBD (25 
mg/ml) delivered in 100 
microlitre actuations by 
a 
pump 
action 
oromucosal spray) vs 
placebo
Change From Baseline in Mean Central Neuropathic Pain at the End of 
Treatment (up to 51 Days) was -0.74 (1.12) for GW-1000-02 and -0.69 
(1.39) for placebo, while change From Baseline in the Mean Percentage of 
Days on Which Escape Medication Was Used at the End of Treatment was
-4.68 (18.25) and -2.91 (20.83) respectively.
GWPharmaceuticals Ltd. A study 
of    cannabis    based    medicine 
extracts  and  placebo  in  patients 
with pain due to spinal cord injury. 
ClinicalTrials.gov. 
http://ClinicalTrials.gov/show/NC 
T01606202.
Accessed April 7, 2014


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Page 59 of 161
Diabetic
painful 
peripheral neuropathy
17
Inhaled
cannabis 
(400mg 
placebo 
or 
active
cannabis 
administered 
via 
the 
Volcano vaporizer)
Center for Medicinal Cannabis 
Research. Efficacy of inhaled 
cannabis 
in 
diabetic 
painful 
peripheral
neuropathy. 
ClinicalTrials.gov.
http:
//ClinicalTrials.gov/show/NCT00 
781001.
Accessed
April 7, 2014
Diabetic
painful 
peripheral neuropathy
Sativex
ongoing
GWPharma Ltd. A double blind, 
randomised, placebo controlled, 
parallel group study of Sativex in 
the treatment of subjects with pain 
due to diabetic neuropathy. EU 
Clinical 
Trials 
Register. 
https://www.clinicaltrialsregister.e 
u/ctrsearch/search?query=eudract
_number:2004
-002530-20. Accessed  August 4,
2014
Peripheral neuropathic pain 
(PNP)
380 patients with 
PNP associated with 
diabetes or allodynia
Delta-9- 
tetrahydrocannabinol(T 
HC)/cannabidiol (CBD) 
oromucosal spray
The pain NRS showed a decrease in score over time in patients from a 
mean of 6.9 points (baseline in the parent studies) to a mean of 4.2 points 
(end of open-label follow-up) (38-week).
Hoggart B, Ratcliffe S, Ehler E, 
Simpson KH, Hovorka J, Lejčko J, 
Taylor L, Lauder H, Serpell M. 
(2015) A multicentre, open-label, 
follow-on study to assess the long- 
term 
maintenance 
of 
effect, 
tolerance and safety of THC/CBD 
oromucosal 
spray 
in 
the 
management of neuropathic pain. J 
Neurol. Jan; 262(1):27-40


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Page 60 of 161
Peripheral neuropathic pain 
(PNP)
303 patients with 
PNP associated with 
allodynia
THC/CBD    spray    vs 
placebo
At the 30% responder level, there were statistically significant treatment 
differences in favour of THC/CBD spray in the full analysis (intention-to- 
treat) dataset [p = 0.034; 95% confidence interval (CI): 1.05-3.70]. There 
was also a reduction in mean PNP 0-10 NRS scores in both treatment 
groups that was numerically higher in the THC/CBD spray group, but 
which failed to reach statistical significance.
Serpell M, Ratcliffe S, Hovorka J, 
et al. (2014) A double-blind, 
randomized, 
placebo-controlled, 
parallel group study of THC/CBD 
spray
in
peripheral 
neuropathic pain treatment. Eur J 
Pain. 18(7):999-1012
Painful  diabetic  peripheral 
neuropathy
16    patients    with 
painful
diabetic 
peripheral 
neuropathy
Placebo   or   low   (1% 
tetrahydrocannabinol 
[THC]),   medium   (4% 
THC),    or   high    (7% 
THC) doses of cannabis 
(Aerosolized    cannabis 
or placebo)
Dose-dependent  reduction  in  diabetic  peripheral  neuropathy  pain  in 
patients with treatment-refractory pain.
Wallace 
MS, 
Marcotte 
TD, 
Umlauf A, Gouaux B, Atkinson JH 
(2015) 
Efficacy 
of 
Inhaled 
Cannabis on Painful Diabetic 
Neuropathy. J Pain. 16(7):616-27


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Page 61 of 161
Painful  diabetic  peripheral 
neuropathy
30 
subjects 
with 
intractable 
PDN 
unresponsive
to
currently 
available treatments
Sativex or placebo
There was a substantial and significant improvement in pain scores in both 
groups over the course of the study. There was, however, no significant 
difference between the two treatment arms for the primary outcome 
measures.
Selvarajah D, Gandhi RA,Witte D, 
Bowler H, Emery C, Tesfaye S. 
(2006) 
Treatment 
of 
painful 
diabetic neuropathy with Sativex 
(a 
cannabis 
based 
medicinal 
product)—results of a randomized 
placebo 
controlled 
trial. 
Diabetologia.     2006;49     (suppl
1):671-672
Diabetic
painful 
peripheral neuropathy
Sativex
The mean daily pain due to diabetic neuropathy on a 0-10 NRS score 
during the last seven days of treatment was assessed
GWPharmaceuticals Ltd. A study 
of sativex® for pain relief due to 
diabetic
neuropathy. 
ClinicalTrials.gov. 
http://ClinicalTrials.gov/show/NC 
T00710424.   Accessed   April   7, 
2014
Refractory human diabetic 
peripheral neuropathic pain 
(DPN)
26
Nabilone, 9 weeks
Improvement in the change in mean end-point neuropathic pain vs placebo 
(mean treatment reduction of 1.27; 95% confidence interval 2.29-0.25, 
P=0.02), with an average nabilone dose at end point of 2.9 ± 1.1mg/day, 
and improvements from baseline for the anxiety subscale of the Hospital 
Anxiety and Depression Scale, the Medical Outcomes Study sleep scale 
problems index, and the European Quality of Life-5-Domains index score 
(each P<0.05).
Toth, C., Mawani, S., Brady, S., 
Chan, C. and others. (2012). An 
enriched-enrolment, 
randomized 
withdrawal, flexible-dose, double- 
blind, placebo-controlled, parallel 
assignment 
efficacy 
study 
of 
nabilone
as
adjuvant 
in 
the 
treatment 
of 
diabetic 
peripheral neuropathic pain. Pain. 
153: 2073-2082


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Page 62 of 161
Adjuvant 
treatment 
in 
painful 
diabeticperipheral 
neuropathy (DPN).
30
Sativex or placebo
Significant improvement in pain scores in both groups, but mean change 
between groups was not significant.
Selvarajah, D., Gandhi, R., Emery,
C. J., and Tesfaye, S. (2010). 
Randomized 
placebo-controlled 
double-blind 
clinical 
trial 
of 
cannabis-based medicinal product 
(Sativex) 
in 
painful 
diabetic 
neuropathy: depression is a major 
confounding factor. Diabetes Care. 
33: 128-130
HIV-related
painful 
peripheral neuropathy
Smoked cannabis
Abrams DI, Jay CA, Vizoso H, et 
al. Smoked cannabis therapy for 
HIV-related 
painful 
peripheral 
neuropathy: 
results 
of 
a 
randomized, 
placebo-controlled 
clinical trial. Paper presented at: 
IACM 
3rd 
Conference 
on 
Cannabinoids 
in 
Medicine; 
September 9-10, 2005; Leiden, the 
Netherlands.
HIV-related
painful 
peripheral neuropathy
Smoked
cannabis: 
Active cannabis (1-8% 
THC by weight) vs 
Placebo cannabis
Center  for  Medicinal  Cannabis 
Research. Medicinal cannabis for 
painful
HIV
neuropathy. 
ClinicalTrials.gov. 
http://ClinicalTrials.gov/show/NC 
T00255580.   Accessed   April   7, 
2014.


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Page 63 of 161
Neuropathic pain of HIV- 
associated
sensory 
neuropathy
50
Cannabis
(3.56% 
tetrahydrocannabinol) or 
identical
placebo 
cigarettes
Smoked cannabis reduced daily pain by 34% (median reduction; IQR = - 
71, -16) vs 17% (IQR = -29, 8) with placebo (p = 0.03). Greater than 30% 
reduction in pain was reported by 52% in thecannabis group and by 24% 
in the placebo group (p = 0.04).
Abrams, D. I., Jay, C. A., Shade, S. 
B., Vizoso, H. and others. (2007). 
Cannabis 
in 
painful 
HIV- 
associated sensory neuropathy: a 
randomized 
placebo-controlled 
trial. Neurology. 68: 515-521
HIV derived pain and other 
medical symptoms
HIV-positive 
individuals 
attending    a    large 
clinic (523)
Cannabis
Patients reported improved appetite (97%), muscle pain (94%), nausea 
(93%), anxiety (93%), nerve pain (90%), depression (86%), and 
paresthesia (85%). Many cannabis users (47%) reported associated 
memory deterioration.
Woolridge, E., Barton, S., Samuel, 
J., Osorio, J. and others. (2005). 
Cannabis use in HIV for pain and 
other medical symptoms. J.Pain 
Symptom.Manage. 29: 358-367.
Pain 
management 
and 
quality of life improvement 
in patients with fibromyalgia
40
Nabilone, from 0.5 mg 
PO at bedtime to 1 mg 
BID over 4 weeks
Significant decreases in the VAS (-2.04, P < .02), FIQ (-12.07, P < .02), 
and anxiety (-1.67, P < .02) in the nabilone treated group at 4 weeks.
Skrabek, R. Q., Galimova, L., 
Ethans, K., and Perry, D. (2008). 
Nabilone for the treatment of pain 
in
fibromyalgia.
J.Pain. 9: 164-173


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Page 64 of 161
Pain and other symptoms in 
patients with IBD
100 patients with 
ulcerative 
colitis 
(UC) 
and 
191 
patients
with
Crohn's
disease 
(CD)    attending   a 
tertiary-care 
outpatient
clinic
completed
a 
questionnaire
Cannabis
Patients were more likely to usecannabis for symptom relief if they had a 
history of abdominal surgery [29/48 (60%) vs. 24/74 (32%); P=0.002], 
chronic analgesic use [29/41 (71%) vs. 25/81 (31%); P<0.001], 
complimentary alternative medicine use [36/66 (55%) vs. 18/56 (32%); 
P=0.01] and a lower short inflammatory bowel disease questionnaire score 
(45.1±2.1 vs. 50.3±1.5; P=0.03).
Lal, S., Prasad, N., Ryan, M., 
Tangri, S. and others. (2011). 
Cannabis use amongst patients 
with inflammatory bowel disease. 
Eur.J.Gastroenterol.Hepatol.    23:
891-896
Acute   inflammatory   pain 
and hyperalgesia
18   healthy   female 
volunteers
Capsules
containing 
Delta- 
tetrahydrocannabinol- 
standardized cannabis 
extract or active placebo 
(orally)
Cannabis extract did not affect heat pain thresholds in the sunburn model. 
Electrical thresholds (250 Hz) were significantly lower compared with 
baseline and placebo. In the capsaicin model, the area of secondary 
hyperalgesia, flare, and spontaneous pain were not altered.
Kraft, 
B., 
Frickey, 
N. 
A., 
Kaufmann, R. M., Reif, M. and 
others. (2008). Lack of analgesia 
by oral standardized cannabis 
extract on acute inflammatory pain 
and hyperalgesia in volunteers. 
Anesthesiology. 109: 101-110


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Page 65 of 161
Chronic pain in patients with 
advanced cancer
43    patients    with 
cancer-related   pain 
experiencing 
inadequate analgesia
 
despite
chronic
opioid 
dosing
Patients 
self-titrated 
THC/CBD spray (n=39) 
or THC spray (n=4)
Long-term use of THC/CBD spray was generally well tolerated, with no 
evidence of a loss of effect for the relief of cancer-related pain with long- 
term use. Furthermore, patients who kept using the study medication did 
not seek to increase their dose of this or other pain-relieving medication 
over time
Johnson JR, Lossignol D, Burnell- 
Nugent M, Fallon MT (2013) An 
open-label extension study to 
investigate the long-term safety 
and tolerability of THC/CBD 
oromucosal spray and oromucosal 
THC spray 
in 
patients with 
terminal 
cancer-related 
pain 
refractory 
to 
strong 
opioid 
analgesics. 
J 
Pain 
Symptom 
Manage. 46(2):207-18
Pain that responds poorly to 
opioid therapy in patients 
with advanced cancer
263
Nabiximols at a low 
dose  (1-4   sprays/day),
medium 
dose 
(6-10 
sprays/day), or high dose 
(11-16 sprays/day)
Efficacy and safety of nabiximols at the 2 lower-dose levels
Portenoy, R. K., Ganae-Motan, E. 
D., Allende, S., Yanagihara, R. 
and others. (2012). Nabiximols for 
opioid-treated
cancer 
patients 
with 
poorly- 
controlled 
chronic 
pain: 
a 
randomized, 
placebo-controlled, 
graded-dose
trial.
J.Pain. 13: 438-449


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Page 66 of 161
Pain
in
patients
with 
advanced cancer
177   patients   with 
cancer   pain,   who 
experienced 
inadequate analgesia
 
despite
chronic
opioid 
dosing
THC:CBD extract (n = 
60), THC extract (n = 
58), or placebo (n = 59)
Twice as many patients taking THC:CBD showed a reduction of more than 
30% from baseline pain NRS score when compared with placebo (23 
[43%] vs. 12 [21%]). The associated odds ratio was statistically significant, 
whereas the number of THC group responders was similar to placebo (12 
[23%] vs. 12 [21%]) and did not reach statistical significance.
Johnson, J. R., Burnell-Nugent, 
M., Lossignol, D., Ganae-Motan,
E. 
D. 
and 
others. 
(2010). 
Multicenter,
double-blind, 
randomized, 
placebo-controlled, 
parallel-group 
study 
of 
the 
efficacy, safety, and tolerability of 
THC:CBD 
extract 
and 
THC 
extract in patients with intractable 
cancer-related 
pain. 
J.Pain 
Symptom.Manage. 39: 167-179
Cancer related pain
10
Placebo and 5, 10, 15, 
and 20 mg THC
Pain relief significantly superior to placebo was demonstrated at high dose 
levels (15 and 20 mg). At these levels, substantial sedation and mental 
clouding were reported.
Noyes, R., Jr., Brunk, S. F., 
Baram, D. A., and Canter, A. 
(1975). Analgesic effect of delta- 
9-tetrahydrocannabinol.
J.Clin.Pharmacol. 15: 139-143


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Page 67 of 161
Chronic pain in patients with 
advanced cancer
43    patients    with 
cancer-related   pain 
experiencing 
inadequate analgesia
 
despite
chronic
opioid 
dosing
Sativex(®)
Long-term safety and 
tolerability
of 
THC/CBD spray and 
THC spray
The efficacy end point of change from baseline in mean Brief Pain 
Inventory-Short Form scores for "pain severity" and "worst pain" domains 
showed a decrease (i.e., improvement) at each visit in the THC/CBD spray 
patients. Similarly, the European Organization for Research and Treatment 
of Cancer Quality of Life Questionnaire-C30 scores showed a decrease 
(i.e., improvement) from baseline in the domains of insomnia, pain, and 
fatigue. No new safety concerns associated with the extended use of 
THC/CBD spray arose.
Johnson, J. R., Lossignol, D., 
Burnell-Nugent,  M.,  and  Fallon,
M. T. (2012). An Open-Label 
Extension Study to Investigate the 
Long-Term 
Safety 
 
and 
Tolerability 
of 
THC/CBD 
Oromucosal 
Spray 
and 
Oromucosal THC Spray  in 
Patients With Terminal Cancer- 
Related Pain Refractory to Strong 
Opioid 
Analgesics. 
J.Pain 
Symptom.Manage.
Chemotherapy
induced 
neuropathic pain
16    patients    with 
established 
chemotherapy- 
induced neuropathic 
pain
Nabiximols
There was no statistically significant difference between the treatment and 
the placebo groups on the NRS-PI. A responder analysis demonstrated that 
there were five participants who reported a two-point or greater reduction 
in pain that trended toward statistical significance and the number needed 
to treat was five.
Lynch ME, Cesar-Rittenberg P, 
Hohmann AG. (2014) A double- 
blind,
placebo-controlled, 
crossover
pilot
trial with extension using an oral 
mucosal cannabinoid extract for 
treatment
of
chemotherapy-induced 
neuropathic
pain.
J
Pain 
SymptomManage. 47(1):166-173


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Page 68 of 161
Experimental heat pain
7 men (mean age =
22.5 years, SD = +/- 
1.5) and 10 women 
(mean age = 23.2 
years, SD = +/- 2.8).
Nabilone single doses of
0.5 and 1 mg
Nabilone did not reduce the global pain intensity experienced during tonic 
heat pain (all values of p > 0.18), also failed to potentiate the strength of 
descending inhibitory responses (all values of p > 43). Nevertheless, at the 
highest dose (1 mg), only for women, nabilone significantly (p = 0.003) 
dampened the temporal summation experienced during the last portion of 
the tonic heat pulse test (i.e., the period of time during which temporal 
summation is greatest).
Redmond, W. J., Goffaux, P., 
Potvin, S., and Marchand, S. 
(2008).
Analgesic
and 
antihyperalgesic 
effects 
of 
nabilone on experimental heat 
pain.    Curr.Med.Res.Opin.    24:
1017-1024.
Electrically induced pain, 
axon 
reflex 
flare, 
and 
psychometric variables in 
FM patients
9 FM patients
2.5-15 mg of delta-9- 
THC, with a weekly 
increase of 2.5 mg, as 
long as no side effects 
were reported
Delta-9-THC had no effect on the axon reflex flare, whereas electrically 
induced pain was significantly attenuated after doses of 10-15 mg delta-9- 
THC (p < 0.05). Daily-recorded pain of the FM patients was significantly 
reduced (p < 0.01).
Schley, M., Legler, A., Skopp, G., 
Schmelz, M. and others. (2006). 
Delta-9-THC based monotherapy 
in 
fibromyalgia 
patients 
on 
experimentally induced pain, axon 
reflex flare, and pain relief. 
Curr.Med.Res.Opin.    22:    1269-
1276.


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Page 69 of 161
Postoperative pain
65
Single 
oral 
dose 
of 
cannabis plant extract 
(Cannador; Institute for 
Clinical Research, IKF, 
Berlin, Germany) (5, 10,
or 15 mg)
These significant dose-related improvements in rescue analgesia 
requirements in the 10 mg and 15 mg groups provide a number needed to 
treat that is equivalent to many routinely used analgesics without frequent 
adverse effects.
Holdcroft, A., Maze, M., Dore, C., 
Tebbs, S. and others. (2006). A 
multicenter dose-escalation study 
of the analgesic and adverse 
effects of an oral cannabis extract 
(Cannador) for postoperative pain 
management.  
 Anesthesiology. 
104: 1040-1046.
Postoperative pain
56 
patients 
with 
moderate to severe 
postoperative 
or 
trauma pain
1.5, 2.0, 2.5, or 3.0 mg
levonantradol or placebo
Significant analgesic effects of each dose of levonantradol as compared to 
placebo (P less than 0.05). However, no significant dose response was 
observed. Side effects: Drowsiness was most frequent. Dry mouth, 
dizziness, "weird dreams," mild hallucinations, nervousness, apprehension 
and confusion occurred less frequently.
Jain, A. K., Ryan, J. R., McMahon,
F. G., and Smith, G. (1981). 
Evaluation 
of 
intramuscular 
levonantradol and placebo in acute 
postoperative
pain. 
J.Clin.Pharmacol. 21: 320S-326S
Postoperative pain
40
women
undergoing  elective 
abdominal 
hysterectomy
Identical 
capsule 
of 
eitheroral delta-9-THC 5 
mg (n=20) or placebo 
(n=20)
There were no significant differences in mean (95% confidence interval of 
the difference) SPID at 6 h between the groups [placebo 7.9, delta-9-THC 
4.3(-1.8 to 9.0)cm h on movement; placebo 8.8, delta-9-THC 4.9(-0.2 to 
8.1)cm h at rest] and time to rescue analgesia [placebo 217, delta-9-THC 
163(-22 to 130)min].
Buggy, D. J., Toogood, L., Maric, 
S., Sharpe, P. and others. (2003). 
Lack of analgesic efficacy of oral 
delta-9-tetrahydrocannabinol 
in 
postoperative pain. Pain. 106: 169-
172


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Page 70 of 161
Postoperative pain
41   patients   (mean 
age  52   +/-  2   yr) 
undergoing 
gynecologic  (46%), 
orthopedic    (44%), 
or
other
(10%) 
surgery
1 mg (n = 11) and 2 mg 
(n = 9) of nabilone, 
ketoprofen 50 mg (n =
11) or placebo (n = 10)
Pain scores at rest and on movement were significantly higher in the 2 mg 
nabilone group compared to the other groups. There were no significant 
differences between groups with respect to episodes of nausea and 
vomiting, quality of sleep, sedation, euphoria, pruritus, or the number and 
severity of adverse events. No serious adverse event was recorded.
Beaulieu, P. (2006). Effects of 
nabilone, a synthetic cannabinoid, 
on
postoperative
pain. 
Can.J.Anaesth. 53: 769-775
Neurogenic
symptoms 
unresponsive 
to 
standard 
treatment, and to quantify 
adverse effects
24 
patients 
with 
multiple 
sclerosis 
(18), 
spinal 
cord 
injury (4), brachial 
plexus damage (1), 
and limb amputation 
due
to
neurofibromatosis 
(1)
Whole-plant extracts of 
delta-9- 
tetrahydrocannabinol 
(THC),
cannabidiol 
(CBD),  1:1  CBD:THC,
or matched placebo (2.5- 
120 mg/24 hours)
Pain relief associated with both THC and CBD was significantly superior 
to placebo. Impaired bladder control, muscle spasms and spasticity were 
improved by CME in some patients with these symptoms. Three patients 
had transient hypotension and intoxication with rapid initial dosing of 
THC-containing CME.
Wade, D. T., Robson, P., House, 
H., Makela, P. and others. (2003). 
A preliminary controlled study to 
determine whether whole-plant 
cannabis extracts can improve 
intractable neurogenic symptoms. 
Clin.Rehabil. 17: 21-29
Fibromyalgia (FM)
56
Cannabis: the route of 
administration 
was 
smoking    (54%),    oral
(46%)   and   combined
(43%)
After 2 hours of cannabis use, VAS scores showed a statistically significant 
(p<0.001) reduction of pain and stiffness, enhancement of relaxation, and 
an increase in somnolence and feeling of well being.
Fiz, J., Duran, M., Capella, D., 
Carbonell, J. and others. (2011). 
Cannabis use in patients with 
fibromyalgia:  
effect  
 
on 
symptoms relief and health-related 
quality of life. PLoS.One. 6: 
e18440


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Page 71 of 161
Fibromyalgia (FM)
40
Nabilone
Effect  of  Nabilone  on  Pain  and  Quality  of  Life  in  Patients  With 
Fibromyalgia
Winnipeg 
Regional 
Health 
Authority; 
Valeant 
Canada 
Limited. A trial assessing the 
effect of nabilone on pain and 
quality of life in patients with 
fibromyalgia. 
ClinicalTrials.gov. 
http://ClinicalTrials.gov/show/NC 
T00272207. Accessed April 7, 
2014
Fibromyalgia (FM)
28 FM patients who 
were cannabis users 
and 28 non-users
Cannabis:
smoking 
(54%),  oral  (46%)  and
combined (43%)
After 2 hours of cannabis use, VAS scores showed a statistically significant 
(p<0.001) reduction of pain and stiffness, enhancement of relaxation, and 
an increase in somnolence and feeling of well being. The mental health 
component summary score of the SF-36 was significantly higher (p<0.05) 
in cannabis users than in non-users. No significant differences were found 
in the other SF-36 domains, in the FIQ and the PSQI.
Fiz, J., Duran, M., Capella, D., 
Carbonell, J. and others. (2011). 
Cannabis use in patients with 
fibromyalgia: effect on symptoms 
relief and health-related quality of 
life. PLoS.One. 6: e18440.-
Headache
128 (survey)
Marijuana,
hashish,
alcoholic
tincture, 
Marinol (5 cases)
Napchan, U., Buse, D. C., and 
Loder, E. W. (2011). The use of 
marijuana
or
synthetic 
cannabinoids for the treatment of 
headache. Headache. 51: 502-505.


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Page 72 of 161
Cluster headache refractory 
to 
multiple 
acute 
and 
preventive medications
1
Marijuana, dronabinol
Successfully aborted attacks with recreational marijuana use; subsequent 
use of dronabinol provided equally effective pain relief.
Robbins, M. S., Tarshish, S., 
Solomon, S., and Grosberg, B. M. 
(2009). Cluster attacks responsive 
to 
recreational 
cannabis 
and 
dronabinol.  Headache.  49:  914-
916.
Cluster
headache
(CH) 
attacks
139
Marijuana
Among the 27 patients (19.4% of the total cohort) who had tried cannabis 
to treat CH attacks, 25.9% reported some efficacy, 51.8% variable or 
uncertain effects, and 22.3% negative effects. Cannabis use is very 
frequent in CH patients, but its efficacy for the treatment of the attacks is 
limited.
Leroux, E., Taifas, I., Valade, D., 
Donnet, A. and others. (2012). Use 
of cannabis among 139 cluster 
headache sufferers. Cephalalgia. 
33: 208-213.
Medication
overuse 
headache (MOH)
30 MOH patients
Nabilone   0.5   mg/day 
versus ibuprofen 400 mg
Improvements from baseline were observed with both treatments. 
However, nabilone was more effective than ibuprofen in reducing pain 
intensity and daily analgesic intake (p < 0.05); moreover, nabilone was the 
only drug able to reduce the level of medication dependence (-41 %, p < 
0.01) and to improve the quality of life (p < 0.05). Side effects were 
uncommon, mild and disappeared when nabilone was discontinued.
Pini LA, Guerzoni S, Cainazzo 
MM, Ferrari A, Sarchielli P, 
Tiraferri 
I, 
Ciccarese 
M, 
Zappaterra M (2012) Nabilone for 
the 
treatment 
of 
medication 
overuse headache: results of a 
preliminary double-blind, active- 
controlled, randomized trial. J 
Headache Pain. 13(8):677-84


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Page 73 of 161
Spasticity   of   spinal   cord 
injured persons
43 questionnaires of 
spinal cord injured 
persons
Various
The  study  suggests  the  need  to  examine  the  relationship  between 
measurable and reported changes in spasticity.
Malec, J., Harvey, R. F., and 
Cayner, J. J. (1982). Cannabis 
effect on spasticity in spinal cord 
injury. 
Arch.Phys.Med.Rehabil. 
63: 116-118.
Spasticity  and  pain  due  to 
spinal cord injury
Comparing 5 mg delta- 
9-tetrahydrocannabinol 
(THC)    p.o.,    50    mg
codeine
p.o.,
and 
placebo
Delta-9-THC and codeine both had an analgesic effect in comparison with 
placebo. Only delta-9-THC showed a significant beneficial effect on 
spasticity.
Maurer, M., Henn, V., Dittrich, A., 
and Hofmann, A. (1990). Delta-9- 
tetrahydrocannabinol
shows 
antispastic and analgesic effects in 
a  single  case  double-blind  trial. 
Eur.Arch.Psychiatry 
Clin.Neurosci. 240: 1-4.
Spasticity   in   people   with 
spinal cord injury(SCI)
12
Nabilone 
or 
placebo 
during the first 4-week 
period (0.5mg once a 
day 
with 
option 
to 
increase to 0.5mg twice 
a day)
There was a significant decrease on active treatment for the Ashworth in 
the most involved muscle (mean difference +/- SD, .909+/-.85; P=.003), 
as well as the total Ashworth score (P=.001). There was no significant 
difference in other measures. Side effects were mild and tolerable.
Pooyania, S., Ethans, K., Szturm, 
T., Casey, A. and others. (2010). A 
randomized, 
double-blinded, 
crossover pilot study assessing the 
effect of nabilone on spasticity in 
persons with spinal cord injury. 
Arch.Phys.Med.Rehabil. 91: 703-
707
Spasticity   in   people   with 
spinal cord injury(SCI)
12
Nabilone or placebo
University  of  Manitoba,  Valeant 
Canada    Limited.    Randomized 
double blind cross over study for 
nabilone  in  spasticity  in  spinal 
cord
injury
persons. 
ClinicalTrials.gov. 
http://ClinicalTrials.gov/show/NC 
T00623376.   Accessed   April   7, 
2014.


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Page 74 of 161
SCI
Twenty-five  
patients   with   SCI 
(three-phase  study), 
individual
dose
adjustment, 
each 
consisting 
of 
6 
weeks
Oral THC (starting with 
a single dose of 10 mg), 
rectal THC-HS, placebo. 
Mean daily doses were 
31 mg with THC and 43 
mg with THC-HS.
Mean SSS for THC decreased significantly from 16.72 (+/-7.60) at 
baseline to 8.92 (+/-7.14) on day 43. Similar improvement was seen with 
THC-HS.
Hagenbach, U., Luz, S., Ghafoor, 
N., Berger, J. M. and others. 
(2007). The treatment of spasticity 
with Delta9-tetrahydrocannabinol 
in persons with spinal cord injury. 
Spinal Cord. 45: 551-562.
Spasticity as a disabling 
complication 
of 
multiple 
sclerosis.
572, 19 weeks
Sativex
or
placebo 
(Phase III)
Intention-to-treat (ITT) analysis showed a highly significant difference in 
favour of nabiximols (P=0.0002). Secondary end-points of responder 
analysis, Spasm Frequency Score, Sleep Disturbance NRS Patient, Carer 
and Clinician Global Impression of Change were all significant in favour 
of nabiximols
Novotna, A., Mares, J., Ratcliffe, 
S., Novakova, I. and others. 
(2011). A randomized, double- 
blind, placebocontrolled, parallel- 
group, enriched-design study of 
nabiximols* (Sativex((R)) ), as 
add-on
therapy,
in 
subjects with refractory spasticity 
caused 
by 
multiple 
sclerosis. 
Eur.J.Neurol. 18: 1122-1131


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Page 75 of 161
Infantile spasms (IS) and 
Lennox-Gastaut 
syndrome 
(LGS)
117 
parents 
of 
children
with 
epilepsy (including 
53 with IS or LGS) 
who
had
administered 
CBD 
products 
to 
their 
children
CBD products
Perceived efficacy and tolerability were similar across etiologic subgroups. 
Eighty-five percent of all parents reported a reduction in seizure frequency, 
and 14% reported complete seizure freedom. Reported side effects were 
far less common during CBD exposure, with the exception of increased 
appetite (30%). A high proportion of respondents reported improvement in 
sleep (53%), alertness (71%), and mood (63%) during CBD therapy.
Hussain SA, Zhou R, Jacobson C, 
Weng J, Cheng E, Lay J, Hung P, 
Lerner JT, Sankar R (2015) 
Perceived efficacy of cannabidiol- 
enriched cannabis extracts for 
treatment of pediatric epilepsy: A 
potential role for infantile spasms 
and 
Lennox-Gastaut 
syndrome. 
Epilepsy Behav. 47:138-41
Spasticity
in
multiple 
sclerosis
Delta-9- 
tetrahydrocannabinol 
(THC)/cannabidiol 
(CBD) [Sativex®]
A significantly greater proportion of THC/CBD than placebo recipients 
achieved a ≥ 30% reduction (a clinically relevant reduction) in spasticity 
severity. The efficacy of THC/CBD has been also shown in at least one 
everyday clinical practice study (MOVE 2). THC/CBD was generally well 
tolerated in clinical trials.
Syed YY, McKeage K, Scott LJ. 
(2014)
Delta-9-
tetrahydrocannabinol/cannabidiol 
(Sativex®): a review of its use in 
patients with moderate to severe 
spasticity due to multiple sclerosis. 
Drugs. 74(5):563-78


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Page 76 of 161
Moderate to severe multiple 
sclerosis spasticity (MSS) 
resistant
to
other 
medications
276
Nabiximols (Sativex®)
After 1 month, nabiximols provided relief of resistant MSS in 74.6% of 
patients according to specialist assessment; mean spasticity 0-10 numerical 
rating scale (NRS) score decreased from 6.1 ± 1.8 to 5.2 ± 2.0 points; in 
patients with NRS improvement ≥20% mean NRS score decreased by 
40%. After 3 months, 55.3% of patients had continued to use nabiximols 
and the mean NRS score had decreased by 25% from baseline. 17% of 
patients reported adverse events
Flachenecker P, Henze T, Zettl 
UK. 
(2014) 
Nabiximols 
(THC/CBD 
oromucosal 
spray, 
Sativex®) in clinical practice-- 
results of a multicenter, non- 
interventional study (MOVE 2) in 
patients with multiple sclerosis 
spasticity. 
Eur 
Neurol. 
71(5- 
6):271-9
Moderate to severe multiple 
sclerosis spasticity (MSS)
52 patients
Nabiximols (Sativex®)
The mean spasticity numerical rating scale (NRS, 0-10) score decreased 
significantly from 6.0 ± 1.8 points at MOVE 2 baseline to 4.8 ± 1.9 points 
after 1 month and remained on this level after 12 months (4.5 ± 2.0 points); 
in patients classified as 'initial responders' (≥20% NRS improvement after 
1 month) similar results were found (baseline: 6.3 ± 1.4 points; after 1
month: 4.0 ± 1.0 points; after 12 months: 4.3 ± 1.9 points). The majority 
of patients (84%) did not report adverse events.
Flachenecker  P,  Henze  T,  Zettl 
UK.
(2014)
Long-term 
effectiveness
and
safety
of 
nabiximols 
(tetrahydrocannabinol/cannabidiol 
oromucosal   spray)   in   clinical 
practice. Eur Neurol. 72(1-2):95- 
102


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Page 77 of 161
Moderate to severe multiple 
sclerosis spasticity (MSS)
300 patients from 42 
specialized
MS
centers
across 
Germany
Nabiximols (Sativex®)
Sativex provided relief of MS-related spasticity in the majority of patients 
who were previously resistant to treatment. In addition, clear 
improvements were noted in MS spasticity-associated symptoms (e.g., 
sleep quality, bladder function and mobility), activities of daily living and 
QoL. Sativex was generally well tolerated.
Flachenecker P (2013) A new 
multiple 
sclerosis 
spasticity 
treatment 
option: 
effect 
in 
everyday clinical practice and 
cost-effectiveness 
in 
Germany. 
Expert Rev Neurother. 13(3 Suppl 
1):15-9
Spasticity   among   patients 
with multiple sclerosis (MS)
50   patients   (42% 
male) with a median 
age 47.8 years (25.6- 
76.8);    38%    were 
diagnosed
with 
primary progressive 
MS,
44%
with 
secondary 
progressive MS, and 
18% with relapsing- 
remitting MS
Inhaled THC/CBD
THC/CBD was effective in 80% of patients at a median dose of 5 (2-10) 
inhalations/day. The adverse event profile consisted of dizziness (11 
patients),  somnolence  (6),  muscle  weakness  (7),  oral  discomfort  (2),
diarrhoea (3), dry mouth (2), blurred vision (2), agitation (1), nausea (1), 
and paranoid ideation (1).
Lorente 
Fernández 
L, 
Monte 
Boquet E, Pérez-Miralles F, Gil 
Gómez I, Escutia Roig M, Boscá 
Blasco 
I, 
Poveda 
Andrés 
JL,Casanova-Estruch 
B 
(2014) 
Clinical 
experiences 
with 
cannabinoids 
in 
spasticity 
management in multiple sclerosis. 
Neurologia. 29(5):257-60


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Page 78 of 161
MS with muscle spasticity
630 patients with 
stable 
MS 
with 
muscle 
spasticity 
from 33 UK centres,
15 week and 12 
months follow up
Oral
Delta(9)- 
tetrahydrocannabinol 
(Delta(9)-THC)
(Dronabinol, 2.5 mg), 
cannabis extract (2.5 mg 
of D9 -THC equivalent,
1.25  mg  of  CBD,  and
,5% other cannabinoids 
per capsule), or placebo.
There was suggestive evidence for treatment effects of Delta(9)-THC on 
some aspects of disability. There were no majorsafety concerns. Overall, 
patients felt that these drugs were helpful in treating their disease.
Zajicek, J., Fox, P., Sanders, H., 
Wright, D. and others. (2003). 
Cannabinoids for treatment of 
spasticity
and
other 
symptoms related 
to multiple 
sclerosis 
(CAMS 
study): 
multicentre randomised placebo- 
controlled
trial.
Lancet.        362:        1517-1526/
Zajicek, J. P., Sanders, H. P., 
Wright, D. E., Vickery, P. J. and 
others. (2005). Cannabinoids in 
multiple
sclerosis
(CAMS) study: safety and efficacy 
data for 12 months follow up. 
J.Neurol.Neurosurg.Psychiatry.
76:
1664-1669
Safety    in    spasticity    in 
multiple sclerosis
33 patients (60% 
female) aged 33-68 
years and a mean 
disease  duration  of
6.6 years
Nabiximols (Sativex®)
THC:CBD oromucosal spray did not adversely influence standard driving 
ability in patients with moderate to severe MS spasticity. No additional 
safety concerns were identified in the registry studies which included 
findings from patients who have been treated for prolonged periods (in the 
German/UK registry 45% of patients had >2 years exposure).
Rekand T. (2014) THC:CBD spray 
and MS spasticity symptoms: data 
from latest studies. Eur Neurol. 71 
Suppl 1:4-9


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Page 79 of 161
Course
of
progressive 
multiple sclerosis
498 patients
Dronabinol or placebo 
for 
36 
months; 
Maximum dose was 28 
mg per day, titrated 
against bodyweight and 
adverse effects.
Dronabinol has no overall effect on the progression of multiple sclerosis 
in the progressive phase.
Zajicek J, Ball S, Wright D, 
Vickery J, Nunn A, Miller D, 
Gomez Cano M, McManus D, 
Mallik S, Hobart J; CUPID 
investigator group. (2013) Effect 
of dronabinol on progression in 
progressive 
multiple 
sclerosis 
(CUPID): a randomised, placebo- 
controlled trial. Lancet Neurol. 
12(9):857-65
Range of symptoms due to 
multiple sclerosis (MS)
160 outpatients with 
MS
Cannabis-based 
medicinal
extract
(CBME)
(Sativex)
containing
equal 
amounts
of
delta-9- 
tetrahydrocannabinol 
(THC)  and  cannabidiol 
(CBD) at a dose of 2.5- 
120 mg of each daily, in 
divided doses.
Reduced from mean (SE) 74.36 (11.1) to 48.89 (22.0) following CBME
and from 74.31 (12.5) to 54.79 (26.3) following placebo [ns]. Spasticity 
VAS scores were significantly reduced by CBME (Sativex) in comparison 
with placebo (P =0.001).
Wade, D. T., Makela, P., Robson, 
P., House, H. and others. (2004). 
Do 
cannabis-based 
medicinal 
extracts have general or specific 
effects on symptoms in multiple 
sclerosis? 
A 
double-blind, 
randomized, 
placebocontrolled 
study on 160 patients. Mult.Scler. 
10: 434-441


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Page 80 of 161
Taste
and
smell 
(chemosensory)perception 
as  well as  appetite, caloric 
intake,  and  quality  of  life 
(QOL)  for  cancer  patients 
with
chemosensory 
alterations
21
patients 
completed the trial
THC         (2.5         mg,
Marinol(®); 
Solvay 
Pharma Inc.) or placebo 
oral capsules twice daily 
for 18 days
Compared with placebo, THC-treated patients reported improved (P = 
0.026) and enhanced (P < 0.001) chemosensory perception and food 'tasted 
better' (P = 0.04). Premeal appetite (P = 0.05) and proportion of calories 
consumed as protein increased compared with placebo (P = 0.008). THC- 
treated patients reported increased quality of sleep (P = 0.025) and 
relaxation (P = 0.045).
Brisbois, T. D., de Kock, I. H., 
Watanabe, S. M., Mirhosseini, M. 
and 
others. 
(2011). 
Delta-9- 
tetrahydrocannabinol
may palliate altered chemosensory 
perception in cancer patients: 
results of a randomized, double- 
blind,
placebo-controlled 
pilot 
trial. 
Ann.Oncol. 22: 2086-2093
Symptoms associated with 
multiple 
sclerosis 
(MS), 
poorly controlled spasticity
57
Cannabis-extract 
capsules standardized to
2.5
mg
tetrahydrocannabinol 
(THC)    and    0.9    mg 
cannabidiol (CBD) each. 
Drug   escalation   phase 
from 15 to maximally 30 
mg THC by 5 mg
No statistically significant differences associated with active treatment 
compared to placebo, but trends in favour of active treatment were seen for 
spasm frequency, mobility and getting to sleep.
Vaney, C., Heinzel-Gutenbrunner, 
M., Jobin, P., Tschopp, F. and 
others. (2004). Efficacy, safety and 
tolerability
of
an orally administered cannabis 
extract 
in 
the 
treatment 
of 
spasticity in patients with multiple 
sclerosis:
a
randomized,
double-blind, 
placebo-controlled, 
crossover 
study. Mult.Scler. 10: 417-424


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Page 81 of 161
Spasticity
in
multiple 
sclerosis
37
Smoked cannabis
Reduction in patient scores on the modified Ashworth scale by an average 
of 2.74 points more than placebo (p < 0.0001). In addition, treatment 
reduced pain scores on a visual analogue scale by an average of 5.28 points 
more than placebo (p = 0.008).
Corey-Bloom, J., Wolfson, T., 
Gamst, A., Jin, S. and others. 
(2012). Smoked 
cannabis 
for 
spasticity
in
multiple 
sclerosis: a randomized, placebo- 
controlled trial. CMAJ. 184: 1143-
1150
Spasticity
caused
by 
multiple sclerosis
189
Oromucosal 
cannabis- 
based  medicine(CBM), 
6 weeks
The primary efficacy analysis on the intention to treat (ITT) population 
showed the active preparation to be significantly superior (P = 0.048). 40% 
of subjects achieved >30% benefit (P = 0.014).
Collin, C., Davies, P., Mutiboko, I. 
K., and Ratcliffe, S. (2007). 
Randomized controlled trial of 
cannabis-based
medicine in spasticity caused by 
multiple sclerosis. Eur.J.Neurol. 
14: 290-296
Spasticity
caused
by 
multiple sclerosis
30
Medicinal Cannabis
Assessment  of Reduction in spasticity as indicated by the: Ashworth 
Spasticity Scale, Timed 25-ft Walk, and Grooved Pegboard Test.
Center  for  Medicinal  Cannabis 
Research.  Short-term  effects  of 
medicinal   cannabis   therapy   on 
spasticity  in   multiple  sclerosis. 
ClinicalTrials.gov. 
http://ClinicalTrials.gov/show/NC 
T00248378.   Accessed   April   7, 
2014


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Page 82 of 161
Spasticity 
and 
other 
symptoms 
in 
multiple 
sclerosis
337 subjects with 
MS spasticity not 
fully relieved with 
current
anti- 
spasticity therapy
Sativex and placebo
The per protocol (PP) population (79% of subjects) change in NRS score 
and responder analyses (> or =30% improvement from baseline) were both 
significantly superior for Sativex, compared with placebo: -1.3 versus -0.8 
points (change from baseline, p=0.035); and 36% versus 24% (responders, 
p=0.040).
Collin C, Ehler E,Waberzinek G, 
et al. (2010) A double-blind, 
randomized, 
placebo-controlled, 
parallel-group study of Sativex, in 
subjects 
with 
symptoms 
of 
spasticity due to multiple sclerosis. 
Neurol Res. 2010;32(5):451-459
Spasticity 
and 
other 
symptoms 
in 
multiple 
sclerosis
137    MS    patients 
with  symptoms  not 
controlled 
satisfactorily   using 
standard drugs
Oromucosal 
cannabis- 
based medicine(CBM), 
average of 434 days
Long-term use of an oromucosal CBM (Sativex) maintains its effect in 
those patients who perceive initial benefit.
Wade, D. T., Makela, P. M., 
House, H., Bateman, C. and others. 
(2006). 
Long-term 
use 
of 
a 
cannabis-based
medicine in the treatment of 
spasticity and other symptoms in 
multiple sclerosis. Mult.Scler. 12: 
639-645
Symptoms  associated  with 
multiple sclerosis (MS)
279
Oral   cannabis   extract 
(CE) or placebo.
The rate of relief from muscle stiffness after 12 weeks was almost twice as 
high with CE than with placebo (29.4% vs. 15.7%; OR 2.26; 95% CI 1.24 
to 4.13; p=0.004, one sided).
Zajicek, J. P., Hobart, J. C., Slade, 
A., Barnes, D. and others. (2012). 
MUltiple Sclerosis and Extract of 
Cannabis:
results of the MUSEC trial. 
J.Neurol.Neurosurg.Psychiatry.
83: 1125-1132


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Page 83 of 161
Symptoms  associated  with 
multiple sclerosis (MS)
72 subjects (36%) 
reported ever having 
used cannabis for 
any 
purpose; 
29 
respondents 
(14%) 
reported continuing 
use of cannabis for 
symptom treatment.
Medical cannabis
The symptoms reported by medical cannabis users to be most effectively 
relieved were stress, sleep, mood, stiffness/spasm, and pain.
Clark, A. J., Ware, M. A., Yazer, 
E., Murray, T. J. and others. 
(2004). Patterns of cannabis use 
among patients with multiple 
sclerosis.  Neurology.  62:  2098-
2100.
Symptoms  associated  with 
multiple sclerosis (MS)
16 patients with MS
Oral
Delta(9)- 
Tetrahydrocannabinol 
(THC)    and    Cannabis 
sativa plant extract
Both drugs were safe, but adverse events were more common with plant- 
extract treatment. Compared with placebo, neither THC nor plant-extract 
treatment reduced spasticity. Both THC and plant-extract treatment 
worsened the participant's global impression.
Killestein J, Hoogervorst ELJ, 
ReifM, et al. (2002) Safety, 
tolerability, and efficacy of orally 
administered cannabinoids in MS. 
Neurology.
2002;
58(9):1404-1407.


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Page 84 of 161
Symptoms  associated  with 
multiple sclerosis (MS)
Smoked cannabis
Hobart JC, Zajicek JP. Cannabis as 
a symptomatic treatment for MS: 
Clinically meaningful MUSEC to 
the stiffness and walking problems 
of 
people 
with 
MS. 
Paper 
presented at: 28th Congress of the 
European 
Committee 
for 
Treatment 
and 
Research 
in 
Multiple Sclerosis; October 10-13, 
2012; Lyon: France. Mult Scler. 
2012; 18(4 suppl 1):247
Symptoms  associated  with 
multiple sclerosis (MS)
Cannabis extract
Zajicek J, Reif M, Schnelle M. 
Cannabis extract in the treatment 
of muscle stiffness and other 
symptoms in multiple sclerosis— 
Results of the MUSEC study. 
Paper presented at: 25th Congress 
of the European Committee for 
Treatment 
and 
Research 
in 
Multiple Sclerosis; September 9- 
12,  2009;  Dusseldorf:  Germany.
Mult    
 Scler.     
 2009;15(9) 
(suppl S):S274
Symptoms  associated  with 
multiple sclerosis (MS)
Orally
administred 
cannabinoids
Killestein J, Hoogervorst ELJ, 
Kalkers NF, et al. The effects of 
orally administred cannabinoids in 
multiple sclerosis patients: a pilot 
study. Mult Scler. 2000;6(1 suppl 
1):S28 doi


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Page 85 of 161
Symptoms  associated  with 
multiple sclerosis (MS)
Cannabis extract
Zajicek J, Reif M, Schnelle M; UK 
MUSEC 
Study 
Investigators. 
Cannabis extract in the treatment 
of muscle stiffness and other 
symptoms in multiple sclerosis – 
results of the MUSEC study. Paper 
presented 
at: 
 
IACM5th 
Conference on Cannabinoids in 
Medicine; October 2-3, 2009; 
Cologne, Germany
Symptoms  associated  with 
multiple sclerosis (MS)
Sativex
Collin C, Ambler Z, Kent R, 
McCalla 
R. 
A 
randomised 
controlled study of Sativex® in 
patients 
with 
symptoms 
of 
spasticity due to multiple sclerosis. 
Paper presented at: 22nd Congress 
of the ECTRIMS; September 27- 
30, 2006; Madrid, Spain.
Symptoms  associated  with 
multiple sclerosis (MS)
Sativex
Robson P,Wade D, Makela P, 
House H, Bateman C. Cannabis- 
based medicinal extract (Sativex) 
produced
significant 
improvements in a subjective 
measure of spasticity which were 
maintained on long-term treatment 
with no evidence of tolerance. 
Paper presented at: IACM 3rd 
Conference on Cannabinoids in 
Medicine; September 9-10, 2005; 
Leiden, the Netherlands


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Page 86 of 161
Progression of MS
493
subjects
with
primary
or
secondary 
progressive, but not 
relapse-remitting, 
MS
Orally administered Δ9- 
THC
Found
no
evidence to support an effect of Δ9-THC on MS progression, as measured 
by
using
either
the
Expanded
Disability 
Status Scale or the Multiple Sclerosis Impact Scale 29 (MSIS-29). 
However,      the       authors       concluded       that       there       was 
some evidence to suggest a beneficial effect in participants who were at 
the      lower      end      of      the      disability       scale       at       the 
time of patient enrolment.
http://sites.pcmd.ac.uk/cnrg/cupid. 
php
The CUPID (Cannabinoid Use in 
Progressive Inflammatory Brain 
Disease) study
Urge incontinence episodes 
without affecting voiding in 
patients 
with 
multiple 
sclerosis
630 (three groups)
Oral  administration  of 
cannabis
extract, 
Delta(9)- 
tetrahydrocannabinol 
(THC)
or
matched 
placebo
Both active treatments showed significant effects over placebo (cannabis 
extract, p=0.005; THC, p=0.039). Adjusted episode rate (i.e. correcting for 
baseline imbalance) from baseline to the end of treatment: cannabis 
extract, 38%; THC, 33%; and placebo, 18%.
Freeman, R. M., Adekanmi, O., 
Waterfield, M. R., Waterfield, A.
E. and others. (2006). The effect of 
cannabis on urge incontinence in 
patients with multiple sclerosis: a 
multicentre, randomised placebo- 
controlled trial (CAMS-LUTS). 
Int.Urogynecol.J.Pelvic.Floor.Dys 
funct. 17: 636-641


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Page 87 of 161
Lower 
urinary 
tract 
symptoms 
(LUTS) 
in 
patients 
with 
multiple 
sclerosis (MS)
21
Extracts
containing 
delta-9- 
tetrahydrocannabinol 
(THC)  and  cannabidiol 
(CBD;  2.5  mg  of  each 
per   spray)   for   eight 
weeks
followed
by 
THC-only (2.5 mg THC 
per spray) for a further 
eight weeks
Patient self-assessment of pain, spasticity and quality of sleep improved 
significantly (P <0.05, Wilcoxon's signed rank test) with pain 
improvement continuing up to median of 35 weeks.
Brady, C. M., DasGupta, R., 
Dalton, C., Wiseman, O. J. and 
others. (2004). An open-label pilot 
study of cannabis-based extracts 
for 
bladder 
dysfunction 
in 
advanced 
multiple 
sclerosis. 
Mult.Scler. 10: 425-433
Multiple sclerosis
420/673 
eligible 
subjects 
(response 
rate 62%) completed 
questionnaires
Medical marijuana
Subjective improvements in symptom experience were reported by the 
majority of people with MS who currently use cannabis.
Page, S. A., Verhoef, M. J., 
Stebbins, R. A., Metz, L. M. and 
others. (2003). Cannabis use as 
described by people with multiple 
sclerosis.   Can.J.Neurol.Sci.   30:
201-205.
Multiple sclerosis
6 men and eight 
women
with 
multiple sclerosis
Medical 
marijuana 
(ranged 
from 
very 
infrequent 
to 
very 
regular)
The perceived benefits of use were consistent with previous reports in the 
literature: reduction in pain, spasms, tremors, nausea, numbness, sleep 
problems, bladder and bowel problems, and fatigue and improved mood, 
ability to eat and drink, ability to write, and sexual functioning. Adverse 
effects included problems with cognition, balance, and fatigue and the 
feeling of being high.
Page, S. A. and Verhoef, M. J. 
(2006). Medicinal marijuana use: 
experiences 
of 
people 
with 
multiple
sclerosis. 
Can.Fam.Physician. 52: 64-65


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Page 88 of 161
Appetite and quality of life 
(QOL) 
in 
patients 
with 
cancer-related 
anorexia- 
cachexia syndrome (CACS)
289
patients 
screened, 243 were 
randomly 
assigned 
and 164 (CE, 66 of 
95 patients; THC, 65 
of 100 patients; and 
PL, 
33 
of 
48 
patients) completed 
treatment
Cannabis  extract  (CE), 
delta-9- 
tetrahydrocannabinol 
(THC),    and    placebo 
(PL).
Intent-to-treat analysis showed no significant differences between the three 
arms for appetite, QOL, or cannabinoid-related toxicity.
Strasser, F., Luftner, D., Possinger, 
K., Ernst, G. and others. (2006). 
Comparison of orally administered 
cannabis
extract
and
delta-9- 
tetrahydrocannabinol in treating 
patients 
with 
cancer-related 
anorexia-cachexia
syndrome: a multicenter, phase III, 
randomized,
double-blind, 
placebo-controlled clinical trial 
from
the
Cannabis-In-Cachexia-Study- 
Group.  J.Clin.Oncol.  24:  3394-
3400
Food intake and body weight
6 
adult 
male 
research volunteers, 
in two groups of 
three subjects each, 
13 days
Two
cigarettes 
containing
active 
marijuana (2.3% delta 9 
THC) or placebo per day
Smoked active marijuana significantly increased total daily caloric intake 
by 40%.
Foltin, R. W., Fischman, M. W., 
and Byrne, M. F. (1988). Effects of 
smoked marijuana on food intake 
and
body
weight of humans living in a 
residential laboratory. Appetite. 
11: 1-14


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Page 89 of 161
Effects across a range of 
behaviors:
eating 
topography, mood, cognitive 
performance, 
physiologic 
measures, and sleep.
10
HIV(+)
marijuana smokers
Dronabinol (5 and 10 
mg) 
and 
marijuana 
(2.0%  and  3.9%  THC)
dose was administered 4 
times daily for 4 days
As compared with placebo, marijuana and dronabinol dose dependently 
increased daily caloric intake and body weight in HIV-positive marijuana 
smokers. Effects of marijuana and dronabinol were comparable, except 
that only marijuana (3.9% THC) improved ratings of sleep.
Haney, M., Gunderson, E. W., 
Rabkin, J., Hart, C. L. and others. 
(2007). Dronabinol and marijuana 
in 
HIV-positive 
marijuana 
smokers. Caloric intake, mood, 
and
sleep.
J.Acquir.Immune.Defic.Syndr. 45:
545-554
Appetite and quality of life 
(QOL) 
in 
patients 
with 
cancer-related 
anorexia- 
cachexia syndrome (CACS)
164
CE (standardized for 2.5 
mg THC and 1 mg 
cannabidiol) or  THC 
(2.5 mg) or PL orally, 
twice daily for 6 weeks
Intent-to-treat analysis showed no significant differences between the three 
arms for appetite, QOL, or cannabinoid-related toxicity. Increased appetite 
was reported by 73%, 58%, and 69% of patients receiving CE, THC, or 
PL, respectively.
Strasser, F., Luftner, D., Possinger, 
K., Ernst, G. and others. (2006). 
Comparison of orally administered 
cannabis
extract
and
delta-9- 
tetrahydrocannabinol in treating 
patients 
with 
cancer-related 
anorexia-cachexia
syndrome: a multicenter, phase III, 
randomized,
double-blind, 
placebo-controlled clinical trial 
from
the
Cannabis-In-Cachexia-Study- 
Group.  J.Clin.Oncol.  24:  3394-
3400
Anorexia  due  to  advanced 
cancer
19
THC 2.5 mg p.o. t.i.d. 
one hour after meals for 
four weeks
Thirteen patients reported an improved appetite
Nelson, K., Walsh, D., Deeter, P., 
and Sheehan, F. (1994). A phase II 
study
of
delta-9- 
tetrahydrocannabinol
for 
appetite stimulation in cancer- 
associated anorexia. J.Palliat.Care. 
10: 14-18


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Page 90 of 161
Palliating  cancer-associated 
anorexia
469
Oral megestrol acetate 
800 
mg/d 
liquid 
suspension plus placebo, 
oral dronabinol 2.5 mg 
twice a day plus placebo, 
or both agents
In the doses and schedules we studied, megestrol acetate provided superior 
anorexia palliation among advanced cancer patients compared with 
dronabinol alone. Combination therapy did not appear to confer additional 
benefit.
Jatoi, A., Windschitl, H. E., 
Loprinzi, C. L., Sloan, J. A. and 
others. (2002). Dronabinol versus 
megestrol
acetate
versus combination therapy for 
cancer-associated 
anorexia: 
a 
North Central Cancer Treatment 
Group
study. J.Clin.Oncol. 20: 567-573
Anorexia nervosa (AN)
11 female patients
Δ9-THC in daily doses 
from 7.5 mg (2.5 mg, 
t.i.d.) to a maximum of 
30 mg (10 mg, t.i.d.), 90 
min
before 
meals, 
for 
a 
period of two weeks.
Δ9-THC  produced  a  weight  gain  equivalent  to  the  active  placebo 
(diazepam)
Gross, H., Ebert, M. H., Faden, V. 
B., Goldberg, S. C. and others. 
(1983). A double-blind trial of 
delta
9-
tetrahydrocannabinol in primary 
anorexia
nervosa.
J.Clin.Psychopharmacol.  3:  165-
171
Severe,
longstanding 
anorexia nervosa (AN)
25 women over 18 
years with AN of at 
least 
5 
years 
duration
Dronabinol, 
2.5 
mg 
twice daily for 4 weeks 
and matching  placebo 
for 4 weeks, separated 
by a 4-week wash-out 
period.
During dronabinol treatment, participants gained 0.73 kg (t = 2.86, df = 22, 
p < 0.01) above placebo without significant psychotropic adverse events.
Andries A, Frystyk J, Flyvbjerg A, 
Støving RK. Dronabinol in severe, 
enduring 
anorexia nervosa: 
a 
randomized controlled trial. Int J 
Eat Disord. 2014 Jan;47(1):18-23


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Page 91 of 161
Anorexia 
and 
disturbed 
behavior in patients with 
Alzheimer's disease
15 patients, 6 weeks
Dronabinol
Body weight of study subjects increased more during the dronabinol 
treatment than during the placebo periods.Dronabinol treatment decreased 
severity of disturbed behavior and this effect persisted during the placebo 
period in patientswho received dronabinol first.
Volicer, L., Stelly, M., Morris, J., 
McLaughlin, J. and others. (1997). 
Effects of dronabinol on anorexia 
and
disturbed
behavior 
in 
patients 
with 
Alzheimer's
disease. 
Int.J.Geriatr.Psychiatry.  12:  913-
919
Weight loss
Placebo, 
5 
mg 
rimonabant, or 20mg 
rimonabant once daily in 
addition 
to 
a 
mild 
hypocaloric diet (600 
kcal/day deficit)
Weight loss at 1 year was significantly greater in patients treated with 
rimonabant 5 mg (mean -3.4 kg [SD 5.7]; p=0.002 vs placebo) and 20 mg 
(-6.6 kg [7.2]; p<0.001 vs placebo) compared with placebo (-1.8 kg [6.4]). 
Significantly morepatients treated with rimonabant 20 mg than placebo 
achieved weight loss of 5% or greater (p<0.001) and 10% or greater 
(p<0.001).
Van Gaal LF, Rissanen AM, 
Scheen AJ, Ziegler O, Rössner S; 
RIO-Europe Study Group. (2005) 
Effects 
of 
the 
cannabinoid-1 
receptor blocker rimonabant on 
weight
reduction
and 
cardiovascularrisk 
factors 
in 
overweight 
patients: 
1-year 
experience from the RIO-Europe 
study.
Lancet.       2005        Apr       16-
22;365(9468):1389-97


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Page 92 of 161
Caloric intake, sleep quality 
in HIV-positive marijuana 
smokers
7,
marijuana 
4.2 ± 2.3 days/week,
Two 
16-day 
stays, 
dronabinol (10 mg QID) 
in one stay and placebo 
in the other
Despite sustained increases in self-reported food cravings, dronabinol only 
increased caloric intake in the initial 8 days of dosing. Similarly, sleep 
quality was improved only in the first 8 days of dosing. Dronabinol's 
mood-enhancing effects were sustained across the 16-day inpatient stay. 
Dronabinol was well tolerated, causing few negative subjective or 
cognitive effects.
Bedi, 
G., 
Foltin, 
R. 
W., 
Gunderson, E. W., Rabkin, J. and 
others. 
(2010). 
Efficacy 
and 
tolerability 
of 
high-dose 
dronabinol maintenance in HIV- 
positive marijuana smokers: a 
controlled 
laboratory 
study. 
Psychopharmacology (Berl). 212:
675-686.
HIV wasting syndrome
39 completed the 
planned 12 weeks of 
study visits
Dronabinol 
2.5 
mg 
twice/day
(D); 
megestrol acetate 750 
mg/day
(M750); 
megestrol   acetate   750
mg/day+dronabinol 2.5 
mg
twice/day 
(M750+D); or megestrol 
acetate
250
mg/day+dronabinol  2.5
mg
twice/day 
(M250+D)
The mean weight change +/- SE over 12 weeks was as follows: D, -2.0 +/- 
1.3 kg; M750, +6.5 +/- 1.1 kg; M750+D, +6.0 +/- 1.0 kg; and M250+D, -
0.3 +/- 1.0 kg (difference among treatment arms, p = 0.0001).
Timpone, J. G., Wright, D. J., Li, 
N., Egorin, M. J. and others. 
(1997). 
The 
safety 
and 
pharmacokinetics of singleagent 
and combination therapy with 
megestrol acetate and dronabinol 
for the treatment of HIV wasting 
syndrome. The DATRI 004 Study 
Group. 
Division 
of 
AIDS 
Treatment 
Research 
Initiative. 
AIDS
Res.Hum.Retroviruses.  13:  305-
315


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Page 93 of 161
AIDS-related anorexia
12 
HIV-infected 
patients 
who had 
had at least a 2.25- 
kg weight loss
Dronabinol 5 mg twice 
daily before meals or 
placebo
During dronabinol treatment, subjects experienced increased percent body 
fat (one percent, p = 0.04); decreased symptom distress (p = 0.04); and 
trends toward weight gain (0.5 kg, p = 0.13), increased prealbumin (29.0 
mg/L, p = 0.11), and improved appetite score (p = 0.14).
Struwe M, Kaempfer SH, Geiger 
CJ,    et    al.     (1997)     Effect 
of dronabinol on nutritional status 
in 
HIV 
infection. 
Ann 
Pharmacother. 27(7-8):827-831
AIDS-related anorexia
139
2.5 mg dronabinol twice 
daily or placebo
Dronabinol was associated with increased appetite above baseline (38% vs 
8% for placebo, P = 0.015), improvement in mood (10% vs -2%, P = 0.06), 
and decreased nausea (20% vs 7%; P = 0.05). Weight was stable in 
dronabinolpatients, while placebo recipients had a mean loss of 0.4 kg (P
= 0.14). Of the dronabinol patients, 22% gained > or = 2 kg, compared with 
10.5% of placebo recipients (P = 0.11).
Beal, J. E., Olson, R., Laubenstein, 
L., Morales, J. O. and others. 
(1995). Dronabinol as a treatment 
for
anorexia
associated with weight loss in 
patients 
with 
AIDS. 
J.Pain 
Symptom.Manage. 10: 89-97
AIDS-related anorexia
94
late-stage 
acquired 
immunodeficiency 
syndrome 
(AIDS)patients 
(mean CD4 count of 
45/mm3), 12
months
Dronabinol
orally-2.5 
mg twice daily (90%) or
2.5 mg once daily (10%)
Dronabinol was associated with a VASH change at least twice baseline and 
stable body weight for at least 7 months
Beal, J. E., Olson, R., Lefkowitz, 
L., Laubenstein, L. and others. 
(1997). Long-term efficacy and 
safety
of
dronabinol 
for acquired immunodeficiency 
syndrome-associated 
anorexia. 
J.Pain Symptom.Manage. 14: 7-14


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Page 94 of 161
Acute effects on caloric 
intake and mood in HIV(+) 
marijuana smokers
30
HIV(+)
marijuana 
smokers 
with and without 
clinically significant 
loss of muscle mass
Dronabinol  (0,  10,  20,
30
mg
p.o.)
and 
marijuana [0.0, 1.8, 2.8, 
3.9%
Delta(9)- 
tetrahydrocannabinol 
(THC)]
Marijuana and dronabinol significantly increased caloric intake in the low 
bioelectrical impedance analysis (BIA) group but not in the normal BIA 
group;drug effects on cognitive performance were minor
Haney, M., Rabkin, J., Gunderson, 
E., and Foltin, R. W. (2005). 
Dronabinol 
and 
marijuana 
in 
HIV(+)
marijuana 
smokers: acute effects on caloric 
intake
and
mood. 
Psychopharmacology (Berl). 181:
170-178
Improvement in quality of 
life, disease activity and 
weight gain in Inflammatory 
bowel disease (IBD) patients
13, 3 months
Inhaled cannabis
Improvement in general health perception (p = 0.001), social functioning 
(p = 0.0002), ability to work (p = 0.0005), physical pain (p = 0.004) and 
depression (p = 0.007). Patients had a weight gain of 4.3 ± 2 kg during 
treatment (range 2-8; p = 0.0002) and an average rise in BMI of 1.4 ± 0.61 
(range 0.8-2.7; p = 0.002). The average Harvey-Bradshaw index was 
reduced from 11.36 ± 3.17 to 5.72 ± 2.68 (p = 0.001).
Lahat, A., Lang, A., and Ben- 
Horin, S. (2012). Impact of 
cannabis treatment on the quality 
of     life,     weight     
 and 
clinical 
disease 
activity 
in 
inflammatory 
bowel 
disease 
patients: a pilot prospective study. 
Digestion. 85: 1-8
Antiemetic effect
13 healthy volunteer 
with ipecac induced 
emesis.
Smoked
marijuana 
cigarettes (8.4 and 16.9 
mg
Delta(9)- 
tetrahydrocannabinol 
[THC])    compared    to 
antiemetic
drug, 
ondansetron (8 mg)
Marijuana  significantly  reduced  ratings  of  "queasiness"  and  slightly 
reduced the incidence of vomiting compared to placebo.
Soderpalm, A. H., Schuster, A., 
and de, Wit H. (2001). Antiemetic 
efficacy of smoked marijuana: 
subjective
and
behavioral 
effects 
on 
nausea 
induced by syrup of ipecac. 
Pharmacol.Biochem.Behav.     69:
343-350


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Page 95 of 161
Antiemetic effect
Levonantradol
and 
Prochlorperazine
Long A,Mioduszewski J, Natale R. 
(1982) A randomized double-blind 
cross-over
comparison 
of the antiemetic activity of 
levonantradol
and 
prochlorperazine. Proc Am Soc 
Clin Oncol. 1: C-220.
Antiemetic effect
THC vs hydroxizine
Broder LE, Lean NL, Hilsenbeck 
SG.
(1982)
A randomized blinded clinical trial 
comparing
delta-9-tetrahydrocannabinol 
(THC)  and  hydroxizine  (HZ)  as 
antiemetics    (AE)    for    cancer 
chemotherapy   (CT).   Proc   Am 
Assoc Cancer Res. ;23:514
Antiemetic effect
36 patients whose 
vomiting
was
refractory
to 
standard antiemetic 
therapy
Oral
delta-9-
tetrahydrocannabinol 
(THC), 15 mg/m2, was 
compared
to
prochlorperazine (PCZ), 
10 mg
THC decreased nausea and vomiting in 23 of 36 (64%) patients compared 
to 1 of 36 receiving PCZ. THC efficacy was not dependent on the class of 
antineoplastic-agent inducing the emetic symptoms, age of patients or type 
of sensorial change experienced.
McCabe M, Smith FP, Macdonald 
JS,Woolley
PV, Goldberg D, Schein PS.(1988) 
Efficacy
of
tetrahydrocannabinol  in  patients 
refractory
to
standard antiemetic therapy. Invest 
New
Drugs.
6(3):243-246


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Page 96 of 161
Antiemetic effect
38 patients receiving 
highly    emetogenic 
chemotherapy 
regimens
(70% 
containing cisplatin)
Butyrophenone 
analogue   domperidone
(D) versus the synthetic 
cannabinoid  nabilone 
(N)
Nausea and food intake scores did not differ significantly, although there 
was a trend towards less nausea and an increased food intake with N. 
Subjectively adverse effects were more frequent with N and included 
drowsiness, dizziness, dry mouth, and postural hypotension. N is superior 
to D for the control of cytotoxic-induced emesis
Pomeroy M, Fennelly JJ, Towers
M. (1986) Prospective randomized 
double-blind trial of nabilone 
versus 
domperidone 
in 
the 
treatment of 
cytotoxic-induced 
emesis. 
Cancer 
Chemother 
Pharmacol. 17(3): 285-288.
Antiemetic effect
18 eligible children, 
aged 10 months to 
17 years
Nabilone
versus 
domperidone
When taking nabilone they experienced significantly fewer vomiting 
episodes and less nausea, and two thirds expressed a preference for the 
drug. The most common side effects of treatment with nabilone were 
somnolence and dizziness, with one patient being disturbed by 
hallucinations.
Dalzell AM, Bartlett H, Lilleyman 
JS. (1986) Nabilone: an alternative 
antiemetic
for
cancer 
chemotherapy. Arch Dis Child. 
61(5):502-505.
Antiemetic effect
16 patients
1 
mg 
levonantradol, 
versus 
10 
mg 
prochlorperazine
There were no statistical differences in patients' responses to levonantradol 
and prochlorperazine. The frequency of side effects was greater with 
levonantradol than with prochlorperazine.
Sheidler VR, Ettinger DS, Diasio 
RB,
Enterline
JP, Brown MD. (1984) Double- 
blind
multiple-dose 
crossover study of the antiemetic 
effect
of
intramuscular
levonantradol 
compared
to
prochlorperazine. 
J 
Clin 
Pharmacol. 24(4):155-159.


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Page 97 of 161
Antiemetic effect
Dronabinol
Harden-Harrison
MM, 
MunsellMF,         Fisch         MJ, 
et al. (2012) Dronabinol for the 
prevention 
of 
nausea 
from 
cyclophosphamide
and/or
adriamycin.
Paper 
presented 
at: 
International 
MASCC/ISOO
Symposium: 
Supportive Care in Cancer; June 
28-30,   2012;   New   York,   NY.
Support
Care
Cancer. 
2012;20:S209-S210.
Antiemetic effect/CINV
16
Whole-plant    cannabis- 
based  medicine  (CBM) 
containing
delta-9- 
tetrahydrocannabinol 
and cannabidiol, taken in 
conjunction
with 
standard therapies in the 
control of CINV.
A higher proportion of patients in the CBM group experienced a complete 
response during the overall observation period [5/7 (71.4%) with CMB vs. 
2/9 (22.2%) with placebo, the difference being 49.2% (95% CI 1%, 75%)], 
due to the delayed period. The incidence of AEs was higher in the CBM 
group (86% vs. 67%). No serious AEs were reported.
Duran M, Pיrez E, Abanades S, et 
al. (2010) Preliminary efficacy and 
safety 
of 
an 
oromucosal 
standardized cannabis extract in 
chemotherapy
induced 
nausea and vomiting. Br J Clin 
Pharmacol. 70(5):656-663
Antiemetic effect/CINV
64 patients
Dronabinol, 
ondansetron,
or
the 
combination
Nausea absence was significantly greater in active treatment groups 
(dronabinol, 71%; ondansetron, 64%; combination therapy, 53%) versus 
placebo (15%; p < 0.05 vs. placebo for all). Nausea intensity and 
vomiting/retching were lowest in patients treated with dronabinol.
Meiri 
E, 
Jhangiani 
H, 
Vredenburgh JJ, et al. (2007) 
Efficacy of dronabinol alone and 
in
combination
with 
ondansetron 
versus 
ondansetron
alone
for 
delayed 
chemotherapy-induced 
nausea
and
vomiting. Curr Med Res Opin. 
23(3):533-543


A P P R O V E D B Y T H E Y A L E U NI V E R SI T Y I R B 9/ 2 7/ 2 0 1 7 V A LI D T H R O U G H 1 0/ 2 5/ 2 0 1 8
Pa ge 9 8  of  1 6 1
A ntie metic  effect/ CI N V
Dr o na bi n ol 
a n d  
pr oc hl or perazi ne  al o ne 
a n d i n c o m bi nati o n
A d diti o n  of  pr oc hl or perazi ne  t o dr o na bi n ol  a p peare d t o decrease  t he 
fre q ue nc y of  d ys p h oric effects  see n wit h t he latter a ge nt. T he  c o m bi nati o n 
was  si g nifica ntl y m ore  effecti ve t ha n was  eit her si n gle a ge nt i n c o ntr olli n g 
c he m ot hera p y-i n d uce d na usea a n d  v o miti n g.
La ne  M,  V o gel  C L,  Fer g us o n  J, et 
al. 
( 1 9 9 1)  
Dr o na bi n ol 
a n d 
pr oc hl or perazi ne  
i n 
c o m bi nati o n      f or      treat me nt 
of  ca ncer c he m ot hera p y-i n d uce d 
na usea
a n d
v o miti n g.  
J 
Pai n  
S y m pt o m  
Ma na ge. 6( 6): 3 5 2- 3 5 9
A ntie metic  effect/ CI N V
2 0
n o nse mi n o mat o us  
testicu lar
ca ncer 
patie nts
Na bil o ne  ( 2 X  2  m g/ da y)
or  aliza pri de ( 3 X  1 5 0  
m g/ da y)  
pri or  
t o 
be gi n ni n g  
l o w- d ose 
cis plati n c he m ot hera p y
Patie nts  o n  na bil o ne  ha d si g nifica ntl y  fe wer e pis o des of  e mesis t ha n t h ose 
o n  aliza pri de ( me dia ns, 1. 1  vs  2. 9;  p  less t ha n 0. 0 1).  Na bil o ne  was  s u peri or 
t o aliza pri de i n gi vi n g  c o m plete relief fr o m na usea  ( me dia ns, 6 5 %  vs  3 0 %;  
p  less t ha n 0. 0 1),  a n d was  m ore  effecti ve i n s h orte ni n g t he d urati o n  of  
na usea  ( me dia ns, 1. 3  h  vs  5. 1  h;  p  less t ha n 0. 0 1);  h o we ver,  it ca use d m ore  
a d verse effects.
Nie derle  N,  Sc h tte J, Sc h mi dt  
C G.  ( 1 9 8 6) Cr oss o ver  c o m paris o n 
of  t he a ntie metic efficac y of  
na bil o ne  a n d aliza pri de i n patie nts  
wit h 
n o nse mi n o mat o us  
testic ular 
ca ncer 
recei vi n g 
cis plati n
th erap y .
Kli n  
W oc he nsc hr. 6 4( 8): 3 6 2- 3 6 5
A ntie metic  effect/ CI N V
2 4
l u n g 
ca ncer 
patie nts 
recei vi n g  
ca ncer 
c he m ot hera p y
2  m g  of  na bil o ne,  or  1 5  
m g of  pr oc hl or perazi ne
Na bil o ne  was  si g nifica ntl y s u peri or t o pr oc hl or perazi ne  i n t he re d ucti o n of  
v o miti n g  e pis o des. Si de  effects, mai nl y  verti g o,  were  e vi de nt i n nearl y  half  
of  t he patie nts  after na bil o ne,  a n d t hree patie nts  were  wit h dra w n  fr o m t he 
st u d y d ue  t o decrease d  c o or di nati o n a n d hall uci nati o ns after na bil o ne.
Niira ne n  A,  Matts o n  K.  ( 1 9 8 5) A  
cr oss- o ver
c o m paris o n 
of  
na bil o ne  
a n d 
p ro ch lo rp erazin e
f or 
e mesis 
i n d uce d 
b y  
ca ncer 
c he m ot hera p y. A m   J  Cli n  
O nc ol.  8( 4): 3 3 6- 3 4 0.


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Page 99 of 161
Antiemetic effect/CINV
57   cancer   patients 
receiving 
chemotherapy
Low-dose levonantradol 
or
standard-dose 
metoclopramide 
and 
crossed over to the other 
antiemetic drug in the 
next
identical 
chemotherapy cycle
Patient preference for antiemetic treatment was levonantradol in 49% and 
metoclopramide in 22% of cases. Levonantradol treatment was 
accompanied by a relatively high incidence of side-effects (71%) 
compared with metoclopramide (29%)
HeimME, QueisserW, Altenburg 
HP.
(1984)
Randomized crossover study of 
the 
antiemetic 
activity 
of 
levonantradol and metoclopramide 
in
cancer 
patients 
receiving 
chemotherapy.
Cancer 
Chemother Pharmacol. 13(2):123-
125
Antiemetic effect/CINV
108 patient
Levonantradol (0.5, 0.75 
or 
1 
mg) 
or 
chlorpromazine (25 mg) 
prior to receiving first 
course 
of 
cytotoxic 
therapy
Levonantradol (0.5 mg) was superior to chlorpromazine (25 mg) as an anti- 
emetic. Both were reasonably well tolerated, although at this dose of 
levonantradol 22% of patients experienced dysphoric reactions. At higher 
doses of levonantradol the proportion of patients experiencing these 
reactions rose to 50%, but without a concomitant increase in antiemetic 
activity. Neither drug achieved satisfactory control of vomiting in patients 
receiving combinations containing cis-platinum.
Hutcheon AW, Palmer JB, Soukop 
M,
et
al.
(1983) 
A randomised multicentre single 
blind
comparison
of 
a 
cannabinoid 
anti-emetic 
(levonantradol)
with 
chlorpromazine 
in 
patients 
receiving
their
first 
cytotoxic chemotherapy. Eur J 
Cancer
Clin
Oncol. 
19(8):1087-1090


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Page 100 of 161
Antiemetic effect/CINV
20    patients    with 
advanced 
gynaecological 
cancer who received 
chemotherapy 
including
cis- 
platinum
Nabilone 3 mg, orally 
three 
times 
a 
day, 
Chlorpromazine  12.5 
mg 
given 
IM, 
15 
minutes before the start 
of cis-platinum
Nabilone, in comparison with chlorpromazine did not significantly reduce 
the number of vomiting. Ten patients preferred nabilone, 5 preferred 
chlorpromazine and 3 were undecided. Predominant side effects noted by 
patients were similar for both agents and included somnolence, dry mouth 
and orthostatic hypotension.
George M, Pejovic MH, Thuaire 
M,
Kramar
A, 
Wolff JP. (1983) [Randomized 
comparative trial of a new anti- 
emetic: nabilone, in  cancer 
patients treated with cisplatin]. 
Biomed  Pharmacother.  37(1):24-
27
Antiemetic effect/CINV
Nabilone
vs
placebo
Jones SE, Durant JR, Greco FA, 
Robertone
A.
(1982) 
A multi-institutional phase III 
study    of    nabilone    
 vs 
placebo in chemotherapy-induced 
nausea
and
vomiting. 
Cancer 
Treat 
Rev. 
9(suppl B):45-48
Antiemetic effect/CINV
Nabilone
vs
placebo
Wada JK, Bogdon DL, Gunnell 
JC,       Hum       GJ,        Gota 
CH, Rieth TE. (1982) Double- 
blind, randomized, crossover trial 
of nabilone vs placebo in cancer 
chemotherapy. Cancer Treat Rev. 
9(suppl B):39-44
Antiemetic effect/CINV
Nabilone
vs.
prochlorperazine
Johansson R, Kilkku P, Groenroos 
M.
(1982)
A double-blind, controlled trial of 
nabilone
vs.
prochlorperazine 
for 
refractory 
emesis 
induced 
by 
cancer 
chemotherapy. Cancer Treat Rev. 
9(suppl
B):25-33


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Page 101 of 161
Antiemetic effect/CINV
55
patients 
harboring a variety 
of neoplasms and 
previously found to 
have severe nausea 
or 
emesis 
from 
antitumor drugs
Delta
9-
Tetrahydrocannabinol 
(THC),
prochlorperazine,
and 
placebo
Nausea was absent in 40 of 55 patients receiving THC, in 8 of 55 patients 
receiving prochlorperazine, and in 5 of 55 in the placebo group. THC 
appeared to be more efficacious in controlling the emesis associated with 
cyclophosphamide, 5-fluorouracil, and doxorubicin and less so for 
nitrogen mustard and the nitrosourea.
Orr LE, McKernan JF. (1981) 
Antiemetic effect of delta 9-
tetrahydrocannabinol
in 
chemotherapy associated nausea 
and emesis as compared to placebo 
and compazine. J Clin Pharmacol. 
21(8-9
suppl):76S-80S
Antiemetic effect/CINV
80
evaluable 
patients 
receiving 
chemotherapy
Nabilone
versus 
prochlorperazine
Sixty patients (75 per cent) reported nabilone to be more effective than 
prochlorperazine for relief of nausea and vomiting. Of these 60 patients, 
46 required further chemotherapy and continued taking nabilone as the 
antiemetic of choice.
Einhorn LH, Nagy C, Furnas B, 
Williams
SD.
(1981) 
Nabilone: an effective antiemetic 
in 
patients 
receiving 
cancer 
chemotherapy. J Clin Pharmacol. 
21(8-9 suppl):64S-69S


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Page 102 of 161
Antiemetic effect/CINV
55
patients 
previously found to 
have severe nausea 
or 
emesis 
from 
antitumor drugs
Tetrahydrocannabinol 
(THC),
prochlorperazine,
and 
placebo
Nausea was absent in 40 of 55 patients receiving THC, eight of 55 patients 
receiving prochlorperazine, and five of 55 in the placebo group. The 
antiemetic effect of THC appeared to be more efficacious for 
cyclophosphamide, fluorouracil, and doxorubicin hydrochloride, and less 
so for mechlorethamine hydrochloride and the nitrosureas.
Orr LE, McKernan JF, Bloome B. 
(1980)Antiemetic
effect   of   tetrahydrocannabinol: 
compared
with
placebo  and  prochlorperazine  in 
chemotherapyassociated
nausea  and  emesis.  Arch  Intern 
Med. 140(11):1431-1433.
Antiemetic effect/CINV
37 patients receiving 
cancer 
chemotherapy
Nabilone given at a dose 
of 2 mg every 12 hours 
versus         slow-release
capsules
of
prochlorperazine 
given 
at a dose of 10 mg every 
12 hours
Eighteen of the 37 patients achieved a complete or partial elimination of 
symptoms: seven with nabilone alone, three with prochlorperazine alone, 
and eight with each drug. Nabilone appeared to be the more effective 
antiemetic for patients who received chemotherapy agents other than high 
dose DDP; it was equivalent to prochlorperazine for those who did receive 
high-dose DDP.
Steele N, Gralla RJ, Braun DWJr, 
Young
CW.
(1980)
Double-blind comparison of the 
antiemetic
effects
of nabilone and prochlorperazine 
on
chemotherapy-induced 
emesis. 
Cancer
Treat
Rep. 
64(2-3):219-224
Antiemetic effect/CINV
25 patients who had 
failed 
to 
benefit 
from
standard 
antiemetic therapy
THC
versus
prochlorperazine 
(compazine)
THC is an effective antiemetic in many patients who receive chemotherapy 
for cancer and for whom other antiemetics are ineffective
Sallan SE, Cronin C, Zelen M, 
Zinberg NE. (1980) Antiemetics in 
patients receiving chemotherapy 
for
cancer: a randomized comparison 
of 
delta-9-tetrahydrocannabinol 
and
prochlorperazine. N Engl J Med. 
302(3):135-138.


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Page 103 of 161
Antiemetic effect/CINV
116
patients 
(median 
age 
61 
years) 
receiving 
combined
5-
fluorouracil
and 
semustine    (methyl 
CCNU) therapy for 
gastrointestinal 
carcinoma
THC, 15 mg orally three 
times
a
day, 
prochlorperazine, 10 mg 
orally three times a day, 
or placebo
The THC had superior antiemetic activity in comparison to placebo, but it 
showed no advantage over prochlorperazine. Central nervous system side- 
effects, however, were significantly more frequent and more severe with 
THC
Frytak S, Moertel CG, O’Fallon 
JR,
et
al.
(1979)
Delta-9 tetrahydrocannabinol as an 
antiemetic
for
patients 
receiving 
cancer 
chemotherapy:
a
comparison
with 
prochlorperazine and a placebo. 
Ann Intern Med. 91(6):825-830
Antiemetic effect/CINV
34 patients with lung 
cancer undergoing a 
3-day schedule of 
chemotherapy with 
Cyclophosphamide, 
Adriamycin 
and 
Etoposide
Nabilone
versus 
Prochlorperazine
Symptom scores were significantly better for patients on nabilone for 
nausea, retching and vomiting (P less than 0.05). Fewer subjects vomited 
with nabilone (P = 0.05) and the number of vomiting episodes was lower 
(P less than 0.05); no patients on nabilone required additional parenteral 
anti-emetic.
Ahmedzai S, Carlyle DL, Calder 
IT,        Moran        F.        (1983)
Anti-emetic efficacy and toxicity 
of 
nabilone, 
a 
synthetic 
cannabinoid, 
in 
lung 
cancer 
chemotherapy. 
Br 
J 
Cancer. 
48(5):657-663


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Page 104 of 161
Antiemetic effect/CINV
214 (75% of whom 
had 
previously 
received Compazine 
with varying results)
Delta-9- 
tetrahydrocannabinol 
(THC)
versus 
prochlorperazine 
(Compazine);
THC was administered 
by body surface area 
(BSA):  BSA  less  than
1.4 m2 = 7.5 mg; BSA 
1.4-1.8 m2 = 10- mg; 
and BSA greater than 
1.8 m2 = 12.5 mg
There were significant drug effects with THC: less ability to concentrate 
(P less than 0.01), less social interaction (P less than 0.05), and less activity 
(P less than 0.05). There were no significant differences between the two 
drugs in the level of food intake or appetite.
Ungerleider JT, Andrysiak T, 
Fairbanks L, Goodnight J, Sarna 
G, Jamison K. (1982) Cannabis 
and 
cancer 
chemotherapy: 
a 
comparison
of
oral
delta-9-THC
and
prochlorperazine.
Cancer. 
50(4):636-645.
Antiemetic effect/CINV
Dronabinol
Grunberg 
SM, 
MunsellMF, 
Morrow PKH, et al. (2012) 
Randomized
double-blind 
evaluation       of       dronabinol 
for 
the 
prevention 
of 
chemotherapy-induced
nausea. Paper presented at: Annual 
Meeting of the American Society 
of Clinical Oncology (ASCO); 1-5 
Jun 2012; Chicago, IL. J Clin 
Oncol.
2012;30(15)(suppl 
1):9061.


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Page 105 of 161
Antiemetic effect/CINV
Dronabinol
versus 
prochlorperazine
Lane M, Vogel CL, Ferguson J, et 
al.
(1989)
Dronabinol 
and 
prochlorperazine 
in 
combination
are
better 
than either single agent alone for 
treatment
of
chemotherapy-induced nausea and 
vomiting.
Proc
Am Soc Clin Oncol. 8:326.
Antiemetic effect/CINV
Nabilone vs placebo
LevittM. 
(1982) 
Nabilone 
vs 
placebo     in     the      treatment 
of chemotherapy-induced nausea 
and
vomiting
in 
cancer patients. Cancer Treat Rev. 
9(suppl B):49-53.
Antiemetic effect/CINV
Nabilone
vs
prochlorperazine
Chan HS, MacLeod SM, Correia 
JA. 
(1984) 
Nabilone 
vs 
prochlorperazine for control of 
cancer 
chemotherapy-induced 
emesis in children. Proc Am Soc 
Clin Oncol. 3:108.
Antiemetic effect/CINV
Dronabinol (10 - 20 mg) 
versus
Ondansetron (8 - 16 mg) 
or 
dronabinol/ondansetron 
(10 - 20 mg/8 - 16 mg)
Solvay
Pharmaceuticals. 
Dronabinol
versus 
standard ondansetron antiemetic 
therapy
in
preventing
delayed-onset 
chemotherapy-induced
nausea
and
vomiting.
ClinicalTrials.gov.
http:
//ClinicalTrials.gov/show/NCT00 
642512
Accessed
April 7, 2014


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Page 106 of 161
Antiemetic effect/CINV
Delta-9- 
tetrahydrocannabinol 
(THC),
prochlorperazine  (PCP) 
and placebo
Frytak S, Moertel CG, Ofallon JR.
Comparison
of 
delta-9-tetrahydrocannabinol 
(THC),
prochlorperazine 
(PCP) 
and 
placebo       as        anti-emetics 
for 
cancer-chemotherapy. 
Proc 
Am 
Assoc 
Cancer 
Res. 
1979;20:391
Antiemetic effect/CINV
Dronabinol
or 
ondansetron alone and 
combined
Jhangiani H, Vredenburgh JJ, 
Barbato 
L, 
et 
al. 
(2005) 
Dronabinol or ondansetron alone 
and
combined
for 
delayed 
chemotherapy-induced 
nausea
and
vomiting (CINV). Blood. 106(11, 
part 2):477B
Antiemetic effect/CINV
Oral
THC
vs 
prochlorperazine
McCabe M, Smith FP, Goldberg 
D,
et
al.
(1981) 
Comparative 
trial 
of 
oral 
9 
tetrahydrocannabinol
and 
prochlorperazine 
for 
cancer 
chemotherapy related nausea and 
vomiting. Proc Am Assoc Cancer 
Res and Am Soc Clin Oncol. 
22:416
Antiemetic effect/CINV
113 patients
Nabilone
vs
prochlorperazine
When both drugs were compared, both nausea (P less than 0.01) and 
vomiting episodes (P less than 0.001) were significantly lower in patients 
given nabilone. Moreover, patients clearly favored nabilone for continued 
use (P less than 0.001).
Herman TS, Einhorn LH, Jones 
SE,
et
al.
(1979)
Superiority 
of 
nabilone 
over 
prochlorperazine as an antiemetic 
in 
patients 
receiving 
cancer 
chemotherapy. N Engl J Med. 
300(23):1295-1297


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Page 107 of 161
Antiemetic effect/CINV
Palonosetron
plus 
dexamethasone with or 
without dronabinol
Melhem-Bertrandt
AI, 
MunsellMF,         Fisch         MJ, 
et al. (2014) A randomized, 
double-blind, 
placebo-controlled 
trial 
of 
palonosetron 
plus 
dexamethasone with or without 
dronabinol
for
the 
prevention 
of 
chemotherapy- 
induced nausea and vomiting after 
moderately
emetogenic 
chemotherapy
[Unpublished 
manuscript]. 2014:1-23
Antiemetic effect/CINV
25
THC
vs.
prochlorperazine 
(compazine)
Sallan, S. E., Cronin, C., Zelen, 
M., and Zinberg, N. E. (1980). 
Antiemetics in patients receiving 
chemotherapy
for
cancer: a randomized comparison 
of 
delta-9-tetrahydrocannabinol 
and
prochlorperazine. 
N.Engl.J.Med.
302: 135-138


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Page 108 of 161
Antiemetic  effect/CINV  in 
children
30  children  3.5  to
17.8 years of age
Nabilone
versus 
prochlorperazine
The overall rate of improvement of retching and emesis was 70% during 
the nabilone and 30% during the prochlorperazine treatment cycles (P =
.003, chi 2 test). On completion of the trial, 66% of the children stated that 
they preferred nabilone, 17% preferred prochlorperazine, and 17% had no 
preference (P = .015, chi 2 test).
Chan HS, Correia JA, MacLeod 
SM. 
(1987) 
Nabilone 
versus 
prochlorperazine for control of 
cancer 
chemotherapy-induced 
emesis
in
children: 
a double-blind, crossover trial. 
Pediatrics. 79 (6):946-952.
Antiemetic  effect/CINV  in 
children
THC
vs.
metoclopramide 
syrup 
and 
prochlorperazine 
tablets
THC was found to be a significantly better antinausea and antivomiting 
agent, but not all patients obtained relief of nausea and vomiting with THC.
Ekert, H., Waters, K. D., Jurk, I. 
H., Mobilia, J. and others. (1979). 
Amelioration 
of 
cancer 
chemotherapy-induced
nausea and vomiting by delta-9- 
tetrahydrocannabinol. Med.J.Aust. 
2: 657-659


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Page 109 of 161
Metabolic
risk
factors,
including adiponectin levels,
in high-risk patients who are 
overweight or obese and 
have dyslipidemia
1036 overweight or
obese patients
Placebo or rimonabant at
a dose of 5 mg or 20 mg 
daily for 12 months
The most frequent adverse events resulting in discontinuation of the drug
were depression, anxiety, and nausea. As compared with placebo, 
rimonabant at a dose of 20 mg was associated with a significant (P<0.001) 
mean weight loss (repeated-measures method, -6.7+/-0.5 kg, and last- 
observation-carried-forward analyses, -5.4+/-0.4 kg), reduction in waist 
circumference (repeated-measures method, -5.8+/-0.5 cm, and last- 
observation-carried-forward analyses, -4.7+/-0.5 cm), increase in HDL 
cholesterol (repeated-measures method, +10.0+/-1.6 percent, and last- 
observation-carried-forward analyses, +8.1+/-1.5 percent), and reduction 
in triglycerides (repeated-measures method, -13.0+/-3.5 percent, and last- 
observation-carried-forward analyses, -12.4+/-3.2 percent). Rimonabant at 
a dose of 20 mg also resulted in an increase in plasma adiponectin levels 
(repeated-measures method, 57.7 percent, and last-observation-carried- 
forward analyses, 46.2 percent; P<0.001), for a change that was partly 
independent of weight loss alone.
Despres,  J.  P.,  Golay,  A.,  and
Sjostrom, L. (2005). Effects of 
rimonabant on metabolic risk 
factors in overweight patients with 
dyslipidemia. N.Engl.J.Med. 353:
2121-2134


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Page 110 of 161
Body 
weight 
and 
cardiometabolic risk factors 
in 
patients 
who 
are 
overweight or obese
3045   obese   (body 
mass   index   >   or
=30)  or  overweight 
(body   mass   index
>27  and  treated  or 
untreated 
hypertension
or 
dyslipidemia)  adult 
patients
Placebo, 
5 
mg/d 
of 
rimonabant, or 20 mg/d 
of rimonabant for 1 year
At year 1, the completion rate was 309 (51%) patients in the placebo group, 
620 (51%) patients in the 5 mg ofrimonabant group, and 673 (55%) 
patients in the 20 mg of rimonabant group. Compared with the placebo 
group, the 20 mg ofrimonabant group produced greater mean (SEM) 
reductions  in  weight  (-6.3  [0.2]  kg  vs  -1.6  [0.2]  kg;  P<.001),  waist
circumference (-6.1 [0.2] cm vs -2.5 [0.3] cm; P<.001), and level of
triglycerides (percentage change, -5.3 [1.2] vs 7.9 [2.0]; P<.001) and a 
greater increase in level of high-density lipoprotein cholesterol (percentage 
change, 12.6 [0.5] vs 5.4 [0.7]; P<.001). Patients who were switched from 
the 20 mg of rimonabant group to the placebo group during year 2 
experienced weight regain
Pi-Sunyer, F. X., Aronne, L. J., 
Heshmati, H. M., Devin, J. and 
others. 
(2006). 
Effect 
of 
rimonabant, 
a 
cannabinoid-1 
receptor blocker, on weight and 
cardiometabolic risk factors in 
overweight or obese patients: RIO- 
North America: a randomized 
controlled trial. JAMA. 295: 761-
775.
Weight loss
1047 overweight or
obese
type
2 
diabetes patients
Placebo 
(n=348), 
5 
mg/day         rimonabant
(360) or 20 mg/day 
rimonabant (339) for 1 
year
Weight loss was significantly greater after 1 year in both rimonabant 
groups than in the placebo group (placebo: -1.4 kg [SD 3.6]; 5 mg/day: - 
2.3 kg [4.2], p=0.01 vs placebo; 20 mg/day: -5.3 kg [5.2], p<0.0001 vs 
placebo).
Scheen, A. J., Finer, N., Hollander, 
P., Jensen, M. D. and others. 
(2006). Efficacy and tolerability of 
rimonabant in overweight or obese 
patients with type 2 diabetes: a 
randomised 
controlled 
study. 
Lancet. 368: 1660-1672


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Page 111 of 161
Weight loss
Placebo, rimonabant 5 or 
20 mg once daily plus a 
calorie-restricted diet for 
2 years
Rimonabant 20 mg over 2 years promoted clinically relevant and durable 
weight loss and improvements incardiometabolic risk factors
Van Gaal, L. F., Scheen, A. J., 
Rissanen, A. M., Rossner, S. and 
others. (2008). Long-term effect of 
CB1 blockade with rimonabant on 
cardiometabolic risk factors: two 
year results from the RIO-Europe 
Study. Eur.Heart J. 29: 1761-1771
Weight loss
5,580
patients
without
diabetes 
(3,165
completed
treatment) and 1,047 
patients
with
diabetes
(692 
completed 
treatment)
Rimonabant (5 or  20 
mg) or placebo for 1 
year
In overweight/obese patients, 20 mg/day rimonabant produced weight loss 
and significant improvements inmultiple cardiometabolic risk factors such 
as waist circumference, A1C, HDL cholesterol, and triglycerides. 
Rimonabant was generally well tolerated, with more frequently reported 
adverse events being gastrointestinal, neurological, and psychiatric in 
nature.
Van Gaal, L., Pi-Sunyer, X., 
Despres, J. P., McCarthy, C. and 
others. (2008). Efficacy and safety 
of rimonabant for improvement of 
multiple 
cardiometabolic 
risk 
factors 
in 
overweight/obese 
patients: pooled 1-year data from 
the Rimonabant in Obesity (RIO) 
program. Diabetes Care. 31 Suppl 
2: S229-S240


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Page 112 of 161
Weight loss
803
abdominally
obese  patients  with
Placebo  or  rimonabant 
atherogenic
20 mg/d for 1 year 
dyslipidemia
Rimonabant decreased abdominal subcutaneous adipose tissue (AT) cross-
sectional area by 5.1% compared to placebo (P<0.005), with a greater 
reduction in visceral AT. Rimonabant significantly reduced liver fat 
content. Systolic (-3.3 mm Hg) and diastolic (-2.4 mm Hg) blood pressure 
were significantly reduced with rimonabant versus placebo (P<0.0001). 
Gastrointestinal, nervous system, psychiatric, and general adverse events 
were more common with rimonabant 20 mg.
Despres, J. P., Ross, R., Boka, G.,
Almeras, N. and others. (2009). 
Effect of rimonabant on the high- 
triglyceride/ low-HDL-cholesterol 
dyslipidemia, 
intraabdominal 
adiposity,    and    liver    fat:    the
ADAGIO-Lipids
trial.
Arterioscler.Thromb.Vasc.Biol.
29: 416-423


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Page 113 of 161
Overweight/obesity
in 
young adults
2566  young  adults
(1264    males    and
1302 females) who 
had data  available 
on cannabis use and 
age of initiation to 
use of cannabis and 
BMI at the 21-year 
follow-up 
(MUSP 
children)
Cannabis,
21-year 
follow-up
Multivariate analysis showed that those who had used cannabis were less 
likely to be categorised in the BMI ≥ 25 group with the least prevalence of 
overweight/obesity being observed in every day cannabis users (odds ratio
= .2; 95% confidence interval [CI]:.1-.4).
Hayatbakhsh, M. R., O'Callaghan,
M. J., Mamun, A. A., Williams, G.
M. and others. (2010). Cannabis 
use and obesity and young adults. 
Am.J.Drug Alcohol Abuse. 36: 
350-356.
Overweight/obesity
US  adults  aged  18 
years or older; -
Cannabis
The prevalence of obesity is lower in cannabis users than in nonusers.
Le Strat, Y. and Le Foll, B. (2011). 
Obesity and cannabis use: results 
from 2 representative national 
surveys.   Am.J.Epidemiol.   174:
929-933


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Page 114 of 161
10 896    adults    in
four groups: non- 
marijuana 
users 
(61.0%),
Diabetes
pastmarijuana  users
(30.7%),  light  (one 
to four times/month) 
(5.0%)   and   heavy 
(more
than
five 
times/month) 
current
marijuana 
users(3.3%)
Cannabis
Marijuana users had a lower age-adjusted prevalence of DM compared to     Rajavashisth, T. B., Shaheen, M.,
non-marijuana users (OR 0.42, 95% CI 0.33 to 0.55; p<0.0001). The Norris, K. C., Pan, D. and others. 
prevalence of elevated C reactive protein (>0.5 mg/dl) was significantly (2012). Decreased prevalence of 
higher (p<0.0001) among non-marijuana users (18.9%) than among past diabetes in marijuana users: cross- 
(12.7%) or current light (15.8%) or heavy (9.2%) users. In a robust sectional data from the National 
multivariate model controlling for socio-demographic factors, laboratory Health and Nutrition Examination 
values and comorbidity, the lower odds of DM among marijuana users was Survey (NHANES) III. BMJ 
significant (adjusted OR 0.36, 95% CI 0.24 to 0.55; p<0.0001).
Open. 2: e000494-


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Page 115 of 161
GI  transit,  gastric  volume 
and satiation
30
healthy
volunteers
Dronabinol  (DRO)  and 
placebo (PLA)
There was an overall retardation of gastric emptying with DRO (P = 
0.018); this was more pronounced in females (P = 0.011), than in males (P
= 0.184). No significant treatment differences were detected for gastric 
volumes, MTV, post-Ensure(R) symptoms, small bowel and colonic 
transit. Fasting gastric volume was greater in males receiving DRO 
compared with PLA (238 +/- 17 vs 185 +/- 16, P = 0.04).
Esfandyari, T., Camilleri, M., 
Ferber, I., Burton, D. and others. 
(2006). Effect of a cannabinoid 
agonist on gastrointestinal transit 
and 
postprandial 
satiation 
in 
healthy 
human 
subjects: 
a 
randomized, 
placebo-controlled 
study. 
Neurogastroenterol.Motil. 
18: 831-838
Colonic
motility
and 
sensation
52 volunteers
Single  dose  of  7.5  mg 
DRO
or
PLA
postoperative
with 
concealed allocation
DRO, relaxes the colon and reduces postprandialcolonic motility and tone. 
Increase in sensation ratings to distension in the presence of relaxation of 
the colon suggests central modulation of perception.
Esfandyari, T., Camilleri, M., 
Busciglio, I., Burton, D. and 
others. 
(2007). 
Effects 
of 
a 
cannabinoid receptor agonist on 
colonic 
motor 
and 
sensory 
functions 
in 
humans: 
a 
randomized, 
placebo-controlled 
study.
Am.J.Physiol 
Gastrointest.Liver Physiol. 293: 
G137-G145


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Page 116 of 161
Colonic 
motility 
and 
sensation in patients with 
IBS
75 individuals with 
IBS (35 with IBS 
with     constipation,
35 with IBS with 
diarrhea, and with 5 
IBS alternating)
1 dose of placebo or 2.5 
mg or 5.0 mg dronabinol
In all patients, dronabinol decreased fasting proximal left colonic MI 
compared with placebo (overall P = .05; for 5 mg dronabinol, P = .046), 
decreased fasting distal left colonic MI (overall P = .08; for 5 mg, P = .13), 
and increased coloniccompliance (P = .058).
Wong, B. S., Camilleri, M., 
Busciglio, I., Carlson, P. and 
others. (2011). Pharmacogenetic 
trial of a cannabinoid agonist 
shows reduced fasting colonic 
motility 
in 
patients 
with 
nonconstipated 
irritable 
bowel 
syndrome. Gastroenterology. 141:
1638-1647
Gut transit in patients with 
IBS
36 IBS-D volunteers
Twice per day PLA (n = 
13), DRO 2.5 mg (n =
10), or DRO 5 mg (n =
13) for 2 days
Overall, DRO 2.5 or 5 mg twice per day for 2 days had no effect on gut 
transit in IBS-D. There appears to be a treatment-by-genotype effect, 
whereby DRO preferentially delays colonic transit in those with the CNR1 
rs806378 CT/TT genotypes.
Wong, B. S., Camilleri, M., 
Eckert, D., Carlson, P. and others. 
(2012).
Randomized 
pharmacodynamic
and 
pharmacogenetic 
trial 
of 
dronabinol effects on colon transit 
in 
irritable 
bowel 
syndrome- 
diarrhea.
Neurogastroenterol.Motil. 
24: 
358-e169
Rectal sensitivity
10 IBS patients and
12
healthy
volunteers (HV)
Placebo and Δ(9) -THC 
(5 and 10 mg in healthy 
volunteers and 10 mg in 
IBS patients)
The cannabinoid agonist Δ(9) -THC did not alter baseline rectal perception 
to distension compared to placebo in HV or IBS patients. Similarly, after 
sigmoid stimulation there were no significant differences between placebo 
and Δ(9) -THC in sensory thresholds of discomfort.
Klooker, T. K., Leliefeld, K. E., 
van den Wijngaard, R. M., and 
Boeckxstaens, G. E. (2011). The 
cannabinoid 
receptor 
agonist 
delta-9-tetrahydrocannabinol does 
not affect visceral sensitivity to 
rectal 
distension 
in 
healthy 
volunteers 
and 
IBS 
patients. 
Neurogastroenterol.Motil. 23: 30-
5


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Page 117 of 161
Crohn's disease (CD)
30
patients
(26 
males) with CD
Medical cannabis
Of the 30 patients 21 improved significantly after treatment with cannabis. 
The average Harvey Bradshaw index improved from 14 +/- 6.7 to 7 +/- 4.7 
(P < 0.001). The need for other medication was significantly reduced.
Naftali, 
T., 
Lev, 
L. 
B., 
Yablecovitch, D., Half, E. and 
others. 
(2011). 
Treatment 
of 
Crohn's disease with cannabis: an 
observational
study. 
Isr.Med.Assoc.J. 13: 455-458
Crohn's disease (CD)
21 patients (mean 
age, 40 ± 14 y; 13 
men)
Twice daily, cigarettes 
containing 115 mg of 
Δ9-
tetrahydrocannabinol(T 
HC)        or        placebo
containing 
cannabis 
flowers from which the 
THC had been extracted
Complete remission (CDAI score, <150) was achieved by 5 of 11 subjects 
in the cannabis group (45%) and 1 of 10 in the placebo group (10%; P =
.43). A clinical response (decrease in CDAI score of >100) was observed 
in 10 of 11 subjects in the cannabis group (90%; from 330 ± 105 to 152 ±
109) and 4 of 10 in the placebo group (40%; from 373 ± 94 to 306 ± 143; 
P = .028).
Naftali T, Bar-Lev Schleider L, 
Dotan I, Lansky EP, Sklerovsky 
Benjaminov 
F, 
Konikoff 
FM 
(2013) Cannabis induces a clinical 
response in patients with Crohn's 
disease: a prospective placebo- 
controlled
study.
Clin 
Gastroenterol
Hepatol. 
11(10):1276-1280
Crohn's disease (CD)
21
chronic
CD 
patients
Medical cannabis
Decrease in the CD activity index >100 in 10 of 11 subjects on cannabis 
compared to 4 of 10 on placebo. Complete remission was achieved in 5 of 
11 subjects in the cannabis group and 1 of 10 in the placebo group.
Naftali T, Mechulam R, Lev LB, 
Konikoff FM. (2014) Cannabis for 
inflammatory bowel disease. Dig 
Dis. 32(4):468-74


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Page 118 of 161
HIV-1 infection (viral load)
67 
patients 
with 
HIV-1 infection, 21 
days
3.95%-
tetrahydrocannabinol 
marijuana   cigarette,   a 
2.5-mg
dronabinol 
(delta-9- 
tetrahydrocannabinol) 
capsule,  or  a  placebo 
capsule three times daily 
before meals
The adjusted average changes in viral load in marijuana and dronabinol 
relative to placebo were -15% (CI, -50% to 34%) and -8% (CI, -37% to 
37%), respectively. Neither CD4+ nor CD8+ cell counts appeared to be 
adversely affected by the cannabinoids.
Abrams, D. I., Hilton, J. F., Leiser,
R. J., Shade, S. B. and others. 
(2003). 
Short-term 
effects 
of 
cannabinoids
in
patients with HIV-1 infection: a 
randomized, 
placebo-controlled 
clinical trial. Ann.Intern.Med. 139: 
258-266
ALS
131 
respondents 
(anonymous survey 
of 
persons 
with 
ALS)
Various (plant derived)
Cannabis may be moderately effective at reducing symptoms of appetite 
loss, depression, pain, spasticity, and drooling. Cannabis was reported 
ineffective in reducing difficulties with speech and swallowing, and sexual 
dysfunction. The longest relief was reported for depression (approximately 
two to three hours).
Amtmann, D., Weydt, P., Johnson,
K. L., Jensen, M. P. and others. 
(2004). Survey of cannabis use in 
patients with amyotrophic lateral 
sclerosis. Am.J.Hosp.Palliat.Care. 
21: 95-104
ALS
Open-label 
crossover    7-month 
treatment
in
20 
patients with ALS
Escalating dose study 
(from 2.5–10 mg) of 
Marinol
Although the study was not powered sufficiently to detect a statistical 
significance in primary efficacy variables (FVC, ALSFRS), symptomatic 
benefits were seen in insomnia, appetite and spasticity.
Gelinas, D. F, Miller, R. G, and 
Abood, M. (2002). Pilot study of 
safety and tolerability of delta 9- 
THC (Marinol) treatment for ALS. 
Amyotroph Lateral Scler Other 
Motor Neuron Disord. 3: 23-24.


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Page 119 of 161
Cramps
in
amyotrophic 
lateral sclerosis
27 
ALS 
patients 
suffering
from 
moderate to severe 
(visual       analogue
scale
(VAS);
VAS≥4)
daily 
cramps
5 mg THC twice daily 
followed by placebo or 
vice versa. Treatment 
period lasted for 2 weeks 
and was preceded by a 2- 
week
drug-free 
observation period (run- 
in, 
wash-out 
period 
respectively).
THC was well tolerated. There was no evidence for a treatment effect on 
cramp intensity, number of cramps, fasciculation intensity or any of the 
other secondary outcome measures.
Weber, M., Goldman, B., and 
Truniger,
S.
(2010). 
Tetrahydrocannabinol (THC) for 
cramps in amyotrophic lateral 
sclerosis: a randomised, double- 
blind
crossover
trial. 
J.Neurol.Neurosurg.Psychiatry.
81: 1135-1140.
Dystonia
secondary
to 
Wilson's disease
1
Smoked cannabis
A patient with generalized  dystonia due to Wilson's disease obtained 
marked improvement in response to smoking cannabis.
Uribe Roca, M. C., Micheli, F., 
and Viotti, R. (2005). Cannabis 
sativa and dystonia secondary to 
Wilson's disease. Mov Disord. 20: 
113-115.
Musician's dystonia
1
THC
General improvement
Jabusch, H. C., Schneider, U., and 
Altenmuller, E. (2004). Delta9- 
tetrahydrocannabinol 
improves 
motor control in a patient with 
musician's dystonia. Mov Disord. 
19: 990-991.


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Page 120 of 161
Dystonic
movement 
disorders
5
Oral 
doses of 
CBD 
rising from 100 to 600 
mg/day over a 6 week
Dose-related improvement in dystonia was observed in all patients and 
ranged from 20 to 50%. Side-effects of CBD were mild and included 
hypotension, dry mouth, psychomotor slowing, lightheadedness, and 
sedation.
Consroe, P., Sandyk, R., and 
Snider, S. R. (1986). Open label 
evaluation 
of 
cannabidiol 
in 
dystonic 
movement 
disorders. 
Int.J.Neurosci. 30: 277-282
Generalised  and  segmental 
primary dystonia
Nabilone
No significant reduction in dystonia following treatment with nabilone.
Fox, S. H., Kellett, M., Moore, A. 
P., Crossman, A. R. and others. 
(2002). 
Randomised, 
double- 
blind, placebo-controlled trial to 
assess the potential of cannabinoid 
receptor 
stimulation 
in 
the 
treatment 
of 
dystonia. 
Mov 
Disord. 17: 145-149
Psychomotor function
19 
male 
chronic, 
daily
cannabis 
smokers
Daily cannabis smokers 
compared to a control 
group of non-intoxicated 
occasional drug users
Chronic cannabis smokers' performance on the CTT (p<0.001) and the 
DAT (p<0.001) was impaired during baseline relative to the comparison 
group. Psychomotor performance in the chronic cannabis smokers 
improved over 3 weeks of abstinence, but did not recover to equivalent 
control group performance.
Bosker WM, Karschner EL, Lee 
D, Goodwin RS, Hirvonen J, Innis 
RB, Theunissen EL, Kuypers KP, 
Huestis MA, Ramaekers JG (2013) 
Psychomotor function in chronic 
daily Cannabis smokers during 
sustained abstinence. PLoS One. 
8(1):e53127


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Page 121 of 161
Huntington's Disease (HD)
15   neuroleptic-free 
patients
with 
Huntington's 
Disease (HD)
Oral 
CBD 
(10 
mg/kg/day for 6 weeks) 
and placebo (sesame oil 
for 6 weeks)
CBD, at an average daily dose of about 700 mg/day for 6 weeks, was 
neither symptomatically effective nor toxic, relative to placebo, in 
neuroleptic-free patients with HD.
Consroe, P., Laguna, J., Allender, 
J., Snider, S. and others. (1991). 
Controlled 
clinical 
trial 
of 
cannabidiol 
in 
Huntington's 
disease.
Pharmacol.Biochem.Behav.     40:
701-708.
Huntington's Disease (HD)
44
Nabilone  (1  or  2  mg) 
versus placebo
Nabilone safe and well tolerated, no psychotic episodes. Assessment of 
either dose of nabilone versus placebo showed a treatment difference of
0.86 (95% CI: -1.8 to 3.52) for total motor score; 1.68 (95% CI: 0.44 to 
2.92) for chorea; 3.57 (95% CI: -3.41 to 10.55) for UHDRS cognition; 4.01 
(95% CI: -0.11 to 8.13) for UHDRS behavior, and 6.43 (95% CI: 0.2 to 
12.66) for the NPI.
Curtis, A., Mitchell, I., Patel, S., 
Ives, N. and others. (2009). A pilot 
study 
using 
nabilone 
for 
symptomatic 
treatment 
in 
Huntington's disease. Mov Disord. 
24: 2254-2259.
Huntington's Disease (HD)
Nabilone
Muller-Vahl, K. R., Schneider, U., 
and 
Emrich, 
H. 
M. 
(1999). 
Nabilone 
increases 
choreatic 
movements 
in 
Huntington's 
disease.  Mov  Disord.  14:  1038-
1040.


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Page 122 of 161
Huntington's disease (HD)
1
Smoked   cannabis   and 
nabilone
The cannabis appeared to improve mood and making patient calmer and 
more relaxed. Improvements in behavior and reduction of chorea 
coinciding with the introduction of cannabis and maintained by daily 
taking nabilone
Curtis, A. and Rickards, H. (2006). 
Nabilone could treat chorea and 
irritability in Huntington's disease. 
J.Neuropsychiatry Clin.Neurosci. 
18: 553-554.
Parkinsonian tremor
5
All patients were given 
on consecutive days: 1) 
marijuana smoked as a 
cigarette, 2) diazepam 5
mg          orally,          3)
levodopa/carbidopa 250 
mg/25 
mg 
orally 
(Sinemet      275),      4)
apomorphine 1 5 mg 
subcutaneously.
None of the patients, including the woman who had previously reported 
benefit, experienced relief or demonstrated improvement of tremor 
following marijuana, despite central effects as evidenced by drowsiness or 
mild euphoria
Frankel, J. P., Hughes, A., Lees, A. 
J., and Stern, G. M. (1990). 
Marijuana 
for 
parkinsonian 
tremor.
J.Neurol.Neurosurg.Psychiatry. 
53: 436.-
Levodopa-induced 
dyskinesia in PD
7
Nabilone
Nabilone significantly reduces levodopa-induced dyskinesia in PD
Sieradzan, K. A., Fox, S. H., Hill,
M., Dick, J. P. and others. (2001). 
Cannabinoids reduce levodopa- 
induced dyskinesia in Parkinson's 
disease: a pilot study. Neurology. 
57: 2108-2111


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Page 123 of 161
Levodopa-induced 
dyskinesia in PD
19
A 
4-week 
dose 
escalation 
of 
orally 
administered cannabis
Cannabis was well tolerated, and had no pro- or antiparkinsonian action. 
There was no evidence for a treatment effect on levodopa-induced 
dyskinesia as assessed by the UPDRS, or any of the secondary outcome 
measures
Carroll, C. B., Bain, P. G., Teare,
L., Liu, X. and others. (2004). 
Cannabis 
for 
dyskinesia 
in 
Parkinson disease: a randomized 
double-blind 
crossover 
study. 
Neurology. 63: 1245-1250.
Symptoms    of    Tourette's 
syndrome
1
Marijuana
Marijuana  appears  to  have  been  an  effective  treatment  modality  for 
symptoms of Tourette's syndrome.
Hemming, M. and Yellowlees, P.
M. (1993). Effective treatment of 
Tourette's 
syndrome 
with 
marijuana.
Journal
of 
Psychopharmacology. 7: 389-391.
Symptoms    of    Tourette's 
syndrome
12 adult TS patients
Single  dose  of  delta9- 
THC at 5.0 to 10.0 mg
Found no significant differences after treatment with delta9-THC 
compared to placebo treatment in verbal and visual memory, reaction time, 
intelligence, sustained attention, divided attention, vigilance, or mood. 
Only when using the Symptom Checklist 90-R (SCL-90-R) data provide 
evidence for a deterioration of obsessive-compulsive behavior (OCB) and 
a trend towards an increase in phobic anxiety
Muller-Vahl, K. R., Koblenz, A., 
Jobges, M., Kolbe, H. and others. 
(2001). Influence of treatment of 
Tourette syndrome with delta9- 
tetrahydrocannabinol 
(delta9- 
THC) 
on 
neuropsychological 
performance.
Pharmacopsychiatry. 34: 19-24.


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Page 124 of 161
Symptoms    of    Tourette's 
syndrome
24 patients with TS
up to 10 mg/day of THC 
vs placebo
Using the TSSL at 10 treatment days (between days 16 and 41) there was 
a significant difference (p <.05) between both groups. Evidence that THC 
is effective and safe in the treatment of tics
Muller-Vahl, K. R., Schneider, U., 
Prevedel, H., Theloe, K. and 
others. 
(2003). 
Delta 
9- 
tetrahydrocannabinol 
(THC) is 
effective in the treatment of tics in 
Tourette syndrome: a 6-week 
randomized
trial.
J.Clin.Psychiatry. 64: 459-465.
Symptoms    of    Tourette's 
syndrome
12 adult TS patients
Single-dose
trial
of 
Delta(9)-THC  (5.0,  7.5
or 10.0 mg)
Using the TSSL, there was a significant improvement of tics (p=0.015) and 
obsessive-compulsive behavior (OCB) (p = 0.041) after treatment with 
Delta(9)-THC compared to placebo. Examiner ratings demonstrated a 
significant difference for the subscore "complex motor tics" (p = 0.015) 
and a trend towards a significant improvement for the subscores "motor 
tics" (p = 0.065), "simple motor tics" (p = 0.093), and "vocal tics" (p = 
0.093). No serious adverse reactions occurred.
Müller-Vahl KR, Schneider U, 
Koblenz A, Jöbges M, Kolbe H, 
Daldrup T, Emrich HM. Treatment 
of Tourette's syndrome with Delta 
9-tetrahydrocannabinol (THC): a 
randomized 
crossover 
trial. 
Pharmacopsychiatry.
2002 
Mar;35(2):57-61


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Page 125 of 161
Sleep in fibromyalgia
Nabilone
Ware M, FitzcharlesMA,  Joseph 
L,
Shir
Y.
The 
effects of nabilone on sleep in 
fibromyalgia:
results 
of a randomized controlled trial. 
Paper
presented
at: 
Canadian 
Rheumatology 
Association Meeting; February 18- 
21, 
2009; 
Kananaskis, 
AB: 
Canada.
Abstract 
149 
J 
Rheumatol. 
2009;36(11):2607
Symptoms    of    Tourette's 
syndrome
24 patients suffering 
from TS
10   mg   Delta(9)-THC 
over a 6-week period
Measuring immediate verbal memory span, we even found a trend towards 
a significant improvement during and after treatment. Results from this 
study corroborate previous data suggesting that in patients suffering from 
TS, treatment with Delta(9)-THC causes neither acute nor long-term 
cognitive deficits.
Müller-Vahl KR, Prevedel H, 
Theloe K, Kolbe H, Emrich HM, 
Schneider 
U. 
Treatment 
of 
Tourette syndrome with delta-9- 
tetrahydrocannabinol 
(delta 
9- 
THC): 
no 
influence 
on 
neuropsychological performance. 
Neuropsychopharmacology. 2003 
Feb;28(2):384-8.
Symptoms    of    Tourette's 
syndrome
28
Delta-9- 
Tetrahydrocannabinol 
(Delta(9)THC), either as 
monotherapy
or
as 
adjuvant  therapy,  with 
placebo
Positive effect from Delta(9)THC, the improvements in tic frequency and 
severity were small and were only detected by some of the outcome 
measures
Curtis, A., Clarke, C. E., and 
Rickards, 
H. 
E. 
(2009). 
Cannabinoids 
for 
Tourette's 
Syndrome.
Cochrane.Database.Syst.Rev. 
CD006565.-


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Page 126 of 161
Sleep in fibromyalgia
Nabilone
Fitzcharles MA, Shir Y, Joseph L, 
Ware MA. (2009) The effects of 
nabilone 
on 
insomnia 
in 
fibromyalgia:
results of a randomized controlled 
trial.
Paper
presented at: American College of 
Rheumatology/ 
Association 
of 
Rheumatology
Health 
Professionals Annual Scientific 
Meeting       (ACR/ARHP       09);
November 6-11, 2009; Atlanta: 
GA. Arthritis Rheum. 60:1429.
Sleep in fibromyalgia
Nabilone   0.5-1mg   vs 
amitriptyline 10-20mg
McGill University Health Center. 
Nabilone versus amitriptyline in 
improving quality of sleep in 
patients 
with 
fibromyalgia. 
ClinicalTrials.gov.
http:
//ClinicalTrials.gov/show/NCT00 
381199
Accessed
April 7, 2014.


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Page 127 of 161
Sleep
disturbance
in 
fibromyalgia (FM)
29
Nabilone (0.5-1.0 mg 
before 
bedtime) 
vs 
amitriptyline (10-20 mg 
before bedtime)
Although sleep was improved by both amitriptyline and nabilone, nabilone 
was superior to amitriptyline (Insomnia Severity Index difference = 3.2; 
95% confidence interval = 1.2-5.3). Nabilone was marginally better on the 
restfulness (Leeds Sleep Evaluation Questionnaire difference = 0.5 [0.0- 
1.0]) but not on wakefulness (difference = 0.3 [-0.2 to 0.8]). No effects on 
pain, mood, or quality of life were observed. AEs were mostly mild to 
moderate and were more frequent with nabilone.
Ware, M. A., Fitzcharles, M. A., 
Joseph, L., and Shir, Y. (2010). 
The effects of nabilone on sleep in 
fibromyalgia: 
results 
of 
a 
randomized 
controlled 
trial. 
Anesth.Analg. 110: 604-610.
Sleep disturbance
17 heavy MJ users 
discontinuing 
MJ 
use and 14 drug-free 
controls. Men and 
women
were 
studied, 18 to 30 
years.
Cannabis
The MJ users showed differences in PSG measures (lower total sleep 
times, and less slow wave sleep than the control group) on both nights; 
they also showed worse sleep efficiency, longer sleep onset, and shorter 
REM latency than the control group on Night 2. More sleep continuity 
parameters were significantly worse for the MJ group than the control 
group on Night 2 versus Night 1, indicating that sleep in the MJ group was 
relatively worse on Night 2 compared to Night 1.
Bolla, K. I., Lesage, S. R., 
Gamaldo, C. E., Neubauer, D. N. 
and 
others. 
(2008). 
Sleep 
disturbance in heavy marijuana 
users. Sleep. 31: 901-908.


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Page 128 of 161
Sleep disturbance
18 heavy MJ users
Cannabis
Across abstinence, Total Sleep Time (TST), Sleep Efficiency (SEff), and 
amount of REM sleep declined, while Wake after Sleep Onset (WASO) 
and Periodic Limb Movements (PLM) increased. Furthermore, quantity 
(joints/week) and duration (years) of MJ use were positively associated 
with more PLMs.
Bolla, K. I., Lesage, S. R., 
Gamaldo, C. E., Neubauer, D. N. 
and
others.
(2010). 
Polysomnogram 
changes 
in 
marijuana users who report sleep 
disturbances 
during 
prior 
abstinence. Sleep  Med. 11: 882-
889.
Obstructive    Sleep    Apnea 
(OSA)
17   adults   with   a 
baseline
Apnea
Hypopnea
Index 
(AHI) ≥15/h
Dronabinol starting at 
2.5 mg once daily. The 
dose 
was 
increased 
weekly, as tolerated, to 
5 mg and finally 
to 
10 mg once daily
Dronabinol treatment is safe and well-tolerated in OSA patients at doses 
of 2.5-10 mg daily and significantly reduces AHI in the short-term.
Prasad 
B, 
Radulovacki 
MG, 
Carley DW. (2013) Proof of 
concept trial of dronabinol in 
obstructive sleep apnea. Front 
Psychiatry. 22;4:1
Somnolence in chronic daily 
cannabis smokers
13 
male 
chronic 
daily
cannabis 
smokers
THC 
doses 
(20 mg) 
around-the-clock for 7 
days (40-120 mg daily)
Higher evening THC and 11-OH-THC concentrations were significantly 
associated with shorter sleep latency, less difficulty falling asleep, and 
more daytime sleep the following day. In contrast, the duration of 
calculated and self-reported nighttime sleep decreased slightly (3.54 and
5.34 minutes per night, respectively) but significantly during the study.
Gorelick 
DA1, 
Goodwin 
RS, 
Schwilke 
E, 
Schroeder 
JR, 
Schwope 
DM, 
Kelly 
DL, 
Ortemann-Renon C, Bonnet D, 
Huestis MA. (2013) Around-the- 
clock oral THC effects on sleep in 
male 
chronic 
daily 
cannabis 
smokers. Am J Addict. 22(5):510- 
4


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Page 129 of 161
Intraocular pressure (IOP)
6 
patients 
with 
ocular hypertension 
or 
early 
primary 
open
angle
glaucoma
Sublingual dose of 5 mg 
Delta-9-THC, 
20 
mg 
CBD,  40  mg  CBD,  or
placebo
Two hours after sublingual administration of 5 mg Delta-9-THC, the IOP 
was significantly lower than after placebo (23.5 mm Hg vs. 27.3 mm Hg, 
P=0.026). The IOP returned to baseline level after the 4-hour IOP 
measurement. CBD administration did not reduce the IOP at any time.
Tomida, I., Azuara-Blanco, A., 
House, H., Flint, M. and others. 
(2006). 
Effect 
of 
sublingual 
application of cannabinoids on 
intraocular pressure: a pilot study. 
J.Glaucoma. 15: 349-353.
Intraocular pressure (IOP)
8
WIN 55212--2, applied 
topically at doses of 25 
or 50 microg
Decreases  the  intraocular  pressure  of  human  glaucoma  resistant  to 
conventional therapies within the first 30 min (15 +/- 0.5% and 23 +/-
0.9%). A maximal reduction of 20 +/- 0.7% and 31 +/- 0.6% is reached in 
the first 60 min.
Porcella, A., Maxia, C., Gessa, G. 
L., and Pani, L. (2001). The 
synthetic cannabinoid WIN55212-
2 
decreases 
the 
intraocular 
pressure 
in 
human 
glaucoma 
resistant to conventional therapies. 
Eur.J.Neurosci. 13: 409-412.
Intraocular pressure (IOP)
1
Marijuana, Marinol
Dramatic effect (lowering).
Zhan, G. L., Camras, C. B., 
Palmberg, P. F., and Toris, C. B. 
(2005). Effects of marijuana on 
aqueous humor dynamics in a 
glaucoma patient. J.Glaucoma. 14: 
175-177


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Page 130 of 161
Arterial
and
intraocular 
hypertension
Systemic 
normotensive (N=8) 
and
hypertensive 
(N=8) open-angle 
glaucoma    patients 
(N=16)
Inhalation
of
tetrahydrocannabinol 
(THC) (2.8%)
The salient observation after THC inhalation was that the changes in ocular 
pressure paralleled the changes in blood pressure in each glaucoma patient. 
These findings suggest that the positive chronotropic response to THC 
tends to maintain cardiac output which limits further decreases in blood 
pressure and the capillary filtration of aqueous humor decreases or the 
reabsorption of aqueous humor increases because of the systemic 
hypotensive effect attending THC inhalation.
Crawford, W. J. and Merritt, J. C. 
(1979).Effects
of 
tetrahydrocannabinol   on   arterial 
and
intraocular
hypertension. 
Int.J.Clin.Pharmacol.Biopharm. 
17: 191-196.
Histamine-evoked 
somatosensory and vascular 
responses
12 
(Study 
1, 
iontophoresis) 
and 
six 
participants 
(Study
2,
microdialysis)
HU210 
(cannabinoid 
receptor agonist) by skin 
patch (50 mM) or dermal 
microdialysis (5 mM)
In humans peripheral administration of a cannabinoid receptor agonist 
attenuates histamine-induced 
itch. The observation 
that protein 
extravasation was not decreased demonstrates that the alleviation of itch is 
not due to an anti-histaminergic property of HU210. The reduced 
neurogenic flare reaction indicates an attenuated antidromic nerve fibre 
activation and neuropeptide release.
Dvorak, 
M., 
Watkinson, 
A., 
McGlone, F., and Rukwied, R. 
(2003). 
Histamine 
induced 
responses are attenuated by a 
cannabinoid receptor agonist in 
human skin. Inflamm.Res. 52: 
238-245.


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Page 131 of 161
Regional cerebral blood flow
10    healthy    male 
volunteers
Oral dose of CBD (400 
mg) or placebo
CBD significantly decreased subjective anxiety and increased mental 
sedation, while placebo did not induce significant changes. Assessment of 
brain regions where anxiolyticeffects of CBD were predicted a priori 
revealed two voxel clusters of significantly decreased ECD uptake in the 
CBD relative to the placebo condition (p<0.001, uncorrected for multiple 
comparisons).
Crippa, J. A., Zuardi, A. W., 
Garrido, G. E., Wichert-Ana, L. 
and others. (2004). Effects of 
cannabidiol (CBD) on regional 
cerebral
blood
flow. 
Neuropsychopharmacology.     29:
417-426
End-stage
open-angle 
glaucoma
9
Either
orally
administered
delta-9- 
tetrahydrocannabinol 
capsules
or
inhaled 
marijuana in addition to 
their existing therapeutic 
regimen
An initial decrease in intraocular pressure was observed in all patients, and 
the investigator's therapeutic goal was met in four of the nine patients. 
However, the decreases in intraocular pressure were not sustained, and all 
patients elected to discontinuetreatment within 1 to 9 months for various 
reasons.
Flach, A. J. (2002). Delta-9- 
tetrahydrocannabinol (THC) in the 
treatment of end-stage open-angle 
glaucoma.
Trans.Am.Ophthalmol.Soc.    100:
215-222


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Page 132 of 161
Heterogenous glaucomas
18
Marihuana inhalation
The hypotensive effects appeared in 60 to 90 minutes as the decrease in 
intraocular pressure(IOP) appeared to follow the decrease in blood 
pressure. In addition to any local effect, the mechanism of lowered to any 
localeffect, the mechanism of lowered IOP may also involve the decreased 
pressure perfusing the ciliary body vasculature as a result of the peripheral 
vasodilatory properties of marihuana.
Merritt, J. C., Crawford, W. J., 
Alexander, P. C., Anduze, A. L. 
and others. (1980). Effect of 
marihuana on intraocular and 
blood 
pressure 
in 
glaucoma. 
Ophthalmology. 87: 222-228.
Specific airway conductance 
(Gaw/VL) and the maximal 
expiratory flow
6   control   and   six 
asthmaticsubjects
10
mg
of
delta9- 
tetrahydrocannabinol
In control subjects, there was a slight but statistically significant increase 
in Gaw/VL after oral administration of delta9-tetrahydrocannabinol; 
however, there was no significant increase in Vmax 50%. One of the 
asthmatic patients developed severe bronchoconstriction following 
administration of delta9-tetrahydrocannabinol; among the remaining five 
patients, there were variable changes in Gaw/VL and Vmax 50% after oral 
administration of delta9-tetrahydrocannabinol, but mean changes were not 
significant.
Abboud, R. T. and Sanders, H. D. 
(1976). 
Effect 
of 
oral 
administration 
of 
delta- 
tetrahydrocannabinol on airway 
mechanics 
in 
normal 
 
and 
asthmatic subjects. Chest. 70: 480-
485


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Page 133 of 161
Bronchial    dynamics    and 
respiratory-center sensitivity
17
normal
volunteers 
with 
previous marihuana 
smoking experience
3.23 mg per kilogram of 
marihuana, using a bag- 
in-box technic
Marihuana smoke, unlike cigarette smoke, causes bronchodilatation rather 
than bronchoconstriction and, unlike opiates, does not cause central 
respiratory depression.
Vachon, L., FitzGerald, M. X., 
Solliday, N. H., Gould, I. A. and 
others. (1973). Single-dose effects 
of marihuana smoke. Bronchial 
dynamics and respiratory-center 
sensitivity in normal subjects. 
N.Engl.J.Med. 288: 985-989.
Acute
pulmonary 
physiologic effects
32
healthy, 
experienced 
male 
marijuana smokers
1  or  2  per  cent  Δ9- 
tetrahydrocannabinol 
(smoking)  or  ingestion 
of 10, 15 and 20 mg of 
Δ9- 
tetrahydrocannabinol
Both smoked marijuana and oral Δ9-tetrahydrocannabinol cause definite 
dilatation of the airways lasting as long as 60 minutes and six hours, 
respectively.
Tashkin, D. P., Shapiro, B. J., and 
Frank, 
I. 
M. 
(1973). 
Acute 
pulmonary physiologic effects of 
smoked marijuana and oral 9 - 
tetrahydrocannabinol in healthy 
young men. N.Engl.J.Med. 289: 
336-341
Plethysmographically 
determined airway resistance 
(Raw)  and  specific  airway 
conductance (SGaw)
10 
subjects 
with 
stable 
bronchial 
asthma
2    per    cent    natural 
marijuana (7 mg per kg) 
and 15 mg of oral Delta- 
9-tetrahydrocannabinol 
(THC) vs placebo
After smoked marijuana, SGaw increased immediately and remained 
significantly elevated (33 to 48 per cent above initial control values) for at 
least 2 hours, whereas SGaw did not change after placebo. After ingestion 
of 15 mg of THC, SGaw was elevated significantly at 1 and 2 hours, and 
Raw was reduced significantly at 1 to 4 hours, whereas no changes were 
noted after placebo.
Tashkin, D. P., Shapiro, B. J., and 
Frank, I. M. (1974). Acute effects 
of smoked marijuana and oral 
delta9-tetrahydrocannabinol 
on 
specific airway conductance in 
asthmatic
subjects. 
Am.Rev.Respir.Dis.    109:    420-
428.


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Page 134 of 161
Experimental   induction   of
acute bronchospasm
8
subjects
with
clinically
stable
500    mg    of    smoked
marijuana (2.0 per cent 
delta9- 
tetrahydrocannabinol) 
compared with those of
500    mg    of    smoked 
placebo  marijuana  (0.0
bronchial asthma
per
cent
delta9-
tetrahydrocannabinol),
0.25 ml of aerosolized 
saline, and 0.25 ml of 
aerosolized
After methacholine-inducedbronchospasm, placebo marijuana and saline Tashkin, D. P., Shapiro, B. J., Lee, 
inhalation produced minimal changes in specific airway conductance and Y. E., and Harper, C. E. (1975). 
thoracic gas volume, whereas 2.0 per cent marijuana and isoproterenol Effects  of  smoked  marijuana  in 
each caused a prompt correction of the bronchospasm and associated experimentally induced asthma. 
hyperinflation
Am.Rev.Respir.Dis.    112:    377-
isoproterenol
(1,250
mug)


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Page 135 of 161
Bronchodilation
Delta
8-
tetrahydrocannabinol 
(delta
8-THC), 
cannabinol  (CBN),  and 
cannabidiol   (CBD)   in 
maximal doses of 75 mg, 
1200 mg, and 1200 mg, 
delta  8-THC  (75  mg), 
delta
9-
tetrahydrocannabinol 
(delta
9-THC), 
combinations   of   CBN 
and CBD with delta 9- 
THC (5 mg)
Delta 9-THC and, to a lesser extent, delta 8-THC, have acute 
bronchodilator activity but that CBN, CBD, and their combinations do not 
provide effective bronchodilation. The daily use of delta 9-THC was not 
associated with clinical tolerance.
Gong, H., Jr., Tashkin, D. P., 
Simmons, M. S., Calvarese, B. and 
others. (1984). Acute and subacute 
bronchial 
effects 
of 
oral 
cannabinoids.
Clin.Pharmacol.Ther. 35: 26-32.
Bronchodilation
10
volunteer 
inpatient asthmatics 
in a steady state
Placebo-ethanol
only; 
delta1- 
tetrahydrocannabinol 
(THC)    200    mug    in 
ethanol;  or  salbutamol
100
mug
(Ventolin 
inhaler)
Salbutamol and THC significantly improved ventilatory function. 
Maximal bronchodilatation was achieved more rapidly with salbutamol, 
but at 1 hour both drugs were equally effective. No cardiovascular or mood 
disturbance was detected, and plasma total cannabinoids at 15 minutes 
were undectable by radioimmunoassay.
Williams, S. J., Hartley, J. P., and 
Graham,
J.
D.
(1976).
Bronchodilator  effect  of  delta1- 
tetrahydrocannabinol administered
 by
aerosol
of 
asthmatic  patients.  Thorax.  31: 
720-723.


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Page 136 of 161
Bronchodilation
Delta1-trans- 
tetrahydrocannabinol, 
(delta1-THC)
It increased peak expiratory flow rate (PEFR) and forced expiratory 
volume in 1 second (FEV1). The rate of onset, magnitude, and duration of 
the bronchodilator effect was dose related.
Hartley, J. P., Nogrady, S. G., and 
Seaton, A. (1978). Bronchodilator 
effect
of
delta1- 
tetrahydrocannabinol.
Br.J.Clin.Pharmacol. 5: 523-525.
Bronchodilation
16 
patients 
with 
proven 
reversible 
airways obstruction
Oral
delta-1-(trans)- 
tetrahydrocannabinol 
(delta-1-THC)
and 
salbutamol
Measurements of forced vital capacity, forced expired volume in one 
second, peak expiratory flow rate, and maximum expiratory flow rate at 50 
percent vital capacity after 10 mg oral delta-1-THC did not differ 
significantly from the effect of placebo, whereas increases after salbutamol 
were significant.
Davies, B. H., Radcliffe, S., 
Seaton, A., and Graham, J. D. 
(1975). A trial of oral delta-1- 
(trans)-tetrahydrocannabinol 
in 
reversible 
airways 
obstruction. 
Thorax. 30: 80-85.
Bronchomotor effect
6  healthy  and  six 
asthmatic subjects
Oral nabilone (2 mg)
Bronchodilation following nabilone was intermediate between that of 
terbutalineand placebo in the healthy subjects but was equivalent to 
placebo in the asthmatics.
Gong, H., Jr., Tashkin, D. P., and 
Calvarese, B. (1983). Comparison 
of bronchial effects of nabilone 
and terbutaline in healthy and 
asthmatic
subjects. 
J.Clin.Pharmacol. 23: 127-133.


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Page 137 of 161
Subacute effects of heavy 
marihuana smoking on the 
lung
28 healthy young 
male 
experienced 
cannabis users
Before and after 47 to 59 
days of daily ad-libitum 
marihuana
smoking 
(mean of 5.2 marihuana 
cigarettes  per  day  per 
subject,   2.2   per   cent 
delta9- 
tetrahydrocannabinol)
After 47 to 59 days of heavy smoking, statistically significant decreases in 
forced expired volume in one second (3 +/- 1 per cent, S.E.), maximal mid- 
expiratory flow rate (11 +/- 2 per cent), plethysmographic specific airway 
conductance (16 +/- 2 per cent) and diffusing capacity (8 +/- 2 per cent) 
were noted as compared with the base-line studies.
Tashkin, D. P., Shapiro, B. J., Lee,
Y. E., and Harper, C. E. (1976). 
Subacute 
effects 
of 
heavy 
marihuana smoking on pulmonary 
function 
in 
healthy 
men. 
N.Engl.J.Med. 294: 125-129.
Cognitive 
function 
in 
patients 
with 
multiple 
sclerosis
Two groups, each of 
25 patients with MS 
(cannabis users and 
nonusers)
Cannabis
Cannabis users performed significantly more poorly than nonusers on 
measures of information processing speed, working memory, executive 
functions, and visuospatial perception. They were also twice as likely as 
nonusers to be classified as globally cognitively impaired. There were no 
between-group differences on the HADS measures of depression and 
anxiety or lifetime SCID-I psychiatric diagnoses.
Honarmand, K., Tierney, M. C., 
O'Connor, P., and Feinstein, A. 
(2011). Effects of cannabis on 
cognitive function in patients with 
multiple sclerosis. Neurology. 76: 
1153-1160.


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Page 138 of 161
Cognitive 
function 
in 
patients 
with 
multiple 
sclerosis
17 
cannabis-naïve 
patientswith 
MS 
were 
assessed 
at 
baseline and at the 
end of the cannabis 
and placebo phases 
of the trial
Free-dose cannabis plant 
extract (Sativex)
Cannabinoid treatment did not induce psychopathology and did not impair 
cognition in cannabis-naïve patientswith MS. However, the positive 
correlation between blood levels of Delta-9-tetrahydrocannabinol and 
psychopathological scores suggests that at dosages higher than those used 
in therapeutic settings, interpersonal sensitivity, aggressiveness, and 
paranoiac features might arise.
Aragona M, Onesti E, Tomassini 
V, Conte A, Gupta S, Gilio F, 
Pantano P, Pozzilli C, Inghilleri M. 
(2009). Psychopathological and 
cognitive effects of therapeutic 
cannabinoids in multiple sclerosis: 
a double-blind, placebo controlled, 
crossover
study.
Clin 
Neuropharmacol. 
Jan- 
Feb;32(1):41-7
Cognitive 
function 
in 
patients 
with 
multiple 
sclerosis
20 subjects with MS 
who
smoked 
cannabis 
and 
19 
noncannabis 
users 
with MS
Cannabis
The cannabis group performed more poorly on the more demanding of the 
Paced Auditory Serial Addition Test tasks (i.e., 2-second version) (p < 
0.02) and the 10/36 Spatial Recall Test (p < 0.03). Cannabis users had more 
diffuse cerebral activation across all N-Back trials and made more errors 
on the 2-Back task (p < 0.006), during which they displayed increased 
activation relative to nonusers in parietal (p < 0.007) and anterior cingulate 
(p < 0.001) regions implicated in working memory.
Pavisian 
B, 
MacIntosh 
BJ, 
Szilagyi G, Staines RW, O'Connor 
P, Feinstein A2. (2014) Effects of 
cannabis on cognition in patients 
with MS: a psychometric and MRI 
study. 
Neurology. 
2014 
May 
27;82(21):1879-87


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Page 139 of 161
Depression
4400  adult  internet 
users
Marijuana daily, once a 
week or less, or never
Daily users reported less depressed mood and more positive affect than 
non-users. The three groups did not differ on interpersonal symptoms. 
Separate analyses for medical vs. recreational users demonstrated that 
medical usersreported more depressed mood and more somatic complaints 
than recreational users, suggesting that medical conditions clearly 
contribute to depression scores and should be considered in studies of 
marijuana and depression.
Denson, T. F. and Earleywine, M. 
(2006). Decreased depression in 
marijuana users. Addict.Behav. 
31: 738-742.
Generalized  social  anxiety 
disorder (SAD)
10   treatment-naïve 
patients with SAD
Oral    dose    of    CBD 
(400 mg) or placebo
Relative to placebo, CBD was associated with significantly decreased 
subjective anxiety (p < 0.001), reduced ECD uptake in the left 
parahippocampal gyrus, hippocampus, and inferior temporal gyrus 
(p < 0.001, uncorrected), and increased ECD uptake in the right posterior 
cingulate gyrus (p < 0.001, uncorrected).
Crippa 
JA, 
Derenusson 
GN, 
Ferrari TB, Wichert-Ana L, Duran 
FL, Martin-Santos R, Simões MV, 
Bhattacharyya S, Fusar-Poli P, 
Atakan Z,Santos Filho A, Freitas- 
Ferrari MC, McGuire PK, Zuardi 
AW, Busatto GF, Hallak JE. 
(2011) Neural basis of anxiolytic 
effects of cannabidiol (CBD) in 
generalized 
social 
anxiety 
disorder:   a   preliminary   report. 
J 
Psychopharmacol. 
2011 
Jan;25(1):121-30


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Page 140 of 161
Generalized  social  anxiety 
disorder (SAD)
24
never-treated 
patients with SAD
CBD (600 mg; n=12) or 
placebo (placebo; n=12)
Pretreatment with CBD significantly reduced anxiety, cognitive 
impairment and discomfort in their speech performance, and significantly 
decreased alert in their anticipatory speech. The placebo group presented 
higher anxiety, cognitive impairment, discomfort, and alert levels when 
compared with the control group as assessed with the VAMS.
Bergamaschi, M. M., Queiroz, R. 
H., Chagas, M. H., de Oliveira, D.
C. and others. (2011). Cannabidiol 
reduces  the  anxiety  induced  by 
simulated    public    speaking    in 
treatment-naive    social    phobia 
patients. 
Neuropsychopharmacology.
36: 
1219-1226
Driving behavior
24
experienced 
driver participants
Dronabinol  (Marinol®;
10   and   20   mg)   and 
placebo
Treatment effects of dronabinol on weaving were comparable with driving 
on the road but inter-individual variability seemed higher in the simulator 
than on the road which may have potential effects on the clinical inferences 
made from simulator driving.
Veldstra JL, Bosker WM, de 
Waard 
D, 
Ramaekers 
JG, 
Brookhuis KA. (2015) Comparing 
treatment effects of oral THC on 
simulated and on-the-road driving 
performance: testing the  validity 
of driving simulator drug research. 
Psychopharmacology 
(Berl). 
232(16):2911-9


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Page 141 of 161
THC induced anxiety
0.5 mg/kg delta 9-THC, 
1 mg/kg CBD, a mixture 
containing 0.5 mg/kg 
delta 
9-THC 
and 
1 
mg/kg CBD and placebo 
and diazepam (10 mg)
CBD blocks the anxiety provoked by delta 9-THC, however this effect also 
extended to marihuana-like effects and to other subjective alterations 
induced by delta 9-THC. This antagonism does not appear to be caused by 
a general block of delta 9-THC effects, since no change was detected in 
the pulse-rate measurements. Several further effects were observed typical 
of CBD and of an opposite nature to those of delta 9-THC.
Zuardi, A. W., Shirakawa, I., 
Finkelfarb, E., and Karniol, I. G. 
(1982). Action of cannabidiol on 
the anxiety and other effects 
produced by delta 9-THC in 
normal
subjects.
Psychopharmacology  (Berl).  76:
245-250
Anxiety
15 healthy men who 
had used cannabis 
15 times or less in 
their life
10 mg of Delta9-THC, 
600 mg of CBD, or a 
placebo
Delta9-Tetrahydrocannabinol increased anxiety, as well as levels of 
intoxication, sedation, and psychotic symptoms, whereas there was a trend 
for a reduction in anxiety following administration of CBD.
Fusar-Poli, P., Crippa, J. A., 
Bhattacharyya, S., Borgwardt, S. J. 
and others. (2009). Distinct effects 
of (26)9-tetrahydrocannabinol and 
cannabidiol on neural activation 
during 
emotional 
processing. 
Arch.Gen.Psychiatry. 66: 95-105.


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Page 142 of 161
Paranoia
121 individuals with 
paranoid ideation
Placebo, THC, or THC 
preceded by a cognitive 
awareness condition
THC significantly increased paranoia, negative affect (anxiety, worry, 
depression, negative thoughts about the self), and a range of anomalous 
experiences, and reduced working memory capacity. The increase in 
negative affect and in anomalous experiences fully accounted for the 
increase in paranoia. Working memory changes did not lead to paranoia.
Freeman D, Dunn G, Murray RM, 
Evans N, Lister R, Antley A, Slater 
M, Godlewska B, Cornish R, 
Williams 
J, 
Di 
Simplicio 
M,Igoumenou A, Brenneisen R, 
Tunbridge 
EM, 
Harrison 
PJ, 
Harmer CJ, Cowen P, Morrison 
PD (2015) How cannabis causes 
paranoia: using the intravenous 
administration
of
∆9- 
tetrahydrocannabinol(THC) 
to 
identify key cognitive mechanisms 
leading to paranoia. Schizophr 
Bull. 41(2):391-9
Psychotic
symptoms 
induced 
by 
Delta-9- 
tetrahydrocannabinol
15 healthy men with 
minimal
earlier
exposure
to 
cannabis
Delta-9- 
tetrahydrocannabinol 
(Delta-9-THC)
and 
Cannabidiol (CBD)
Delta-9-THC and CBD had opposite effects on activation relative to 
placebo in the striatum during verbal recall, in the hippocampus during the 
response inhibition task, in the amygdala when subjects viewed fearful 
faces, in the superior temporal cortex when subjects listened to speech, and 
in the occipital cortex during visual processing. Delta-9-THC and CBD 
can have opposite effects on regional brain function, which may underlie 
their different symptomatic and behavioral effects, and CBD's ability to 
block the psychotogenic effects of Delta-9-THC.
Bhattacharyya, S., Morrison, P. D., 
Fusar-Poli, P., Martin-Santos, R. 
and 
others. 
(2010). 
Opposite 
effects
of
delta-9- 
tetrahydrocannabinol
and 
cannabidiol 
on 
human 
brain 
function 
and 
psychopathology. 
Neuropsychopharmacology.     35:
764-774.


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Page 143 of 161
Posttraumatic stress disorder 
(PTSD)
47
patients 
diagnosed
with 
PTSD   and   having 
continuing 
nightmares  in  spite 
of
conventional 
antidepressants  and 
hypnotics
Nabilone
The majority of patients (72%) receiving nabilone experienced either 
cessation of nightmares or a significant reduction in nightmare intensity. 
Subjective improvement in sleep time, the quality of sleep, and the 
reduction of daytime flashbacks and nightsweats were also noted by some 
patients.
Fraser, G. A. (2009). The use of a 
synthetic 
cannabinoid 
in 
the 
management of treatment-resistant 
nightmares in posttraumatic stress 
disorder
(PTSD).
CNS.Neurosci.Ther. 15: 84-88
Posttraumatic stress disorder 
(PTSD)
Canadian 
male 
military 
personnel 
with PTSD
Nabilone
capsules 
(NAB) 
0.5mg 
to 
maximum of 3.0mg or 
placebo (PBO)
NAB provided significant relief for military personnel with PTSD, The 
mean reduction in nightmares as measured by the CAPS Recurring and 
Distressing Dream scores were -3.6 ± 2.4 and -1.0 ± 2.1 in the NAB and 
PBO groups, respectively (p=0.03).
Jetly R, Heber A, Fraser G, 
Boisvert D (2015) The efficacy of 
nabilone, a synthetic cannabinoid, 
in 
the 
treatment 
of 
PTSD- 
associated 
nightmares: 
A 
preliminary randomized, double- 
blind, placebo-controlled cross- 
over
design
study. 
Psychoneuroendocrinology.
51:585-8
PTSD
104 male inmates 
with serious mental 
illness
Nabilone 4.0 mg
Results indicated significant improvement in PTSD-associated insomnia, 
nightmares, PTSD symptoms, and Global Assessment of Functioning and 
subjective improvement in chronic pain. There was no evidence of abuse 
within this high-risk population or reduction of efficacy when nabilone 
was given in powder form with water rather than as a capsule.
Cameron C, Watson D, Robinson J 
(2015) 
Use 
of 
a 
synthetic 
cannabinoid 
in 
a correctional 
population for posttraumatic stress 
disorder-related 
insomnia 
and 
nightmares, chronic pain, harm 
reduction, and other indications: a 
retrospective 
evaluation. 
J 
ClinPsychopharmacol. 34(5):559-
64


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Page 144 of 161
Nighttime
agitation
in 
patients with dementia
6
consecutive 
patients  in  the  late 
stages  of  dementia 
and  suffering  from 
circadian
and 
behavioral 
disturbances-five 
patients
with 
Alzheimer's  disease 
and one patient with 
vascular dementia
2.5 mg dronabinol daily 
for 2 weeks
Compared to baseline, dronabinol led to a reduction in nocturnal motor 
activity (P=0.028). These findings were corroborated by improvements in 
Neuropsychiatric Inventory total score (P=0.027) as well as in subscores 
for agitation, aberrant motor, and nighttime behaviors (P<0.05). No side 
effects were observed.
Walther, 
S., 
Mahlberg, 
R., 
Eichmann, U., and Kunz, D. 
(2006).
Delta-9-
tetrahydrocannabinol
for 
nighttime 
agitation 
in 
severe 
dementia. 
Psychopharmacology 
(Berl). 185: 524-528.
Dementia-related agitation
1
Nabilone (initially 0.5 
mg at bedtime, and then 
twice per day)
Immediate reduction in the severity of agitation and resistiveness and 
eventual improvement in various behavioural symptoms following six 
weeks of continuous treatment
Passmore, M. J. (2008). The 
cannabinoid 
receptor 
agonist 
nabilone for the treatment of 
dementia-related
agitation. 
Int.J.Geriatr.Psychiatry.  23:  116-
117.


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Page 145 of 161
Agitation 
and 
aggressive 
behavior 
in 
severely 
demented patients
40 inpatients
Dronabinol
The addition of dronabinol to patients' treatment regimens was associated 
with significant decreases in all domains of the Pittsburgh Agitation Scale. 
There were also significant improvements in Clinical Global Impression 
scores, sleep duration and percentage of meals consumed during the 
treatment periods. Twenty-six adverse events were recorded during 
dronabinoltreatment, none of which led to medication discontinuation.
Woodward MR, Harper DG2, 
Ellison JM2. (2014) Dronabinol 
for the treatment of agitation and 
aggressive behavior in acutely 
hospitalized severely demented 
patients 
with 
noncognitive 
behavioral 
symptoms. 
Am 
J 
Geriatr Psychiatry. 22(4):415-9
Dementia-related 
neuropsychiatric   symptoms 
(NPS)
24 patients received
THC
and
26 
received placebo
THC 1.5 mg or matched 
placebo (1:1) 3 times 
daily for 3 weeks
This study provides Class I evidence that for patients with dementia- 
related NPS, low-dose THC does not significantly reduce NPS at 21 days, 
though it is well-tolerated.
van den Elsen GA, Ahmed AI, 
Verkes RJ, Kramers C, Feuth T, 
Rosenberg PB, van der Marck 
MA, Olde Rikkert MG (2015). 
Tetrahydrocannabinol
for 
neuropsychiatric 
symptoms 
in 
dementia: 
A 
randomized 
controlled 
trial. 
Neurology. 
9;84(23):2338-46


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Page 146 of 161
Emotional processing
48 volunteers
THC
(8mg),
CBD 
(16mg),
THC+CBD
(8mg+16mg)
and 
placebo, by inhalation
In comparison to placebo, CBD improved emotional facial affect 
recognition at 60% emotional intensity; THC was detrimental to the 
recognition of ambiguous faces of 40% intensity. The combination of 
THC+CBD produced no impairment. Relative to placebo, both THC alone 
and combined THC+CBD equally increased feelings of being 'stoned'. 
CBD did not influence feelings of 'stoned'.
Hindocha 
C1, 
Freeman 
TP2, 
Schafer G2, Gardener C2, Das 
RK2, Morgan CJ3, Curran HV 
(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. 
2015 
Mar;25(3):325-34
Progressive
Inflammatory 
brain Disease (CUPID)
Patients
were 
randomised in a 2 : 1 
ratio to Δ(9)-THC or 
placebo;
Adults 
aged   18-65   years 
with    primary    or 
secondary 
progressive
MS 
(493 (329 active and
164 placebo))
Oral
Δ(9)-THC
(maximum 
28 mg/day) 
or 
matching placebo; 
Visits - Three and 6 
months, and then 6- 
monthly up to 36 or 42 
months.
The CUPID trial failed to demonstrate a significant treatment effect in 
primary or secondary outcomes. There were no major safety concerns, but 
unwanted side effects seemed to affect compliance. The intervention had 
significant additional costs with no improvement in health outcomes; 
therefore, it was dominated by usual care and not cost-effective.
Ball S, Vickery J, Hobart J, Wright 
D, Green C, Shearer J, Nunn A, 
Cano MG, MacManus D, Miller 
D, Mallik S, Zajicek J (2015) The 
Cannabinoid Use in Progressive 
Inflammatory 
brain 
Disease 
(CUPID) 
trial: 
a 
randomised 
double-blind 
placebo-controlled 
parallel-group multicentre trial and 
economic 
evaluation 
of 
cannabinoids to slow progression 
in 
multiple 
sclerosis. 
Health 
Technol
Assess.
2015
Feb;19(12):vii-viii,  xxv-xxxi,  1-
187.


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Page 147 of 161
Antitumoral action
9
patients
with 
recurrent 
glioblastoma 
multiforme
THC intratumoraly
Cannabinoid delivery was safe and could be achieved without overt 
psychoactive effects. Median survival of the cohort from the beginning of 
cannabinoid administration was 24 weeks (95% confidence interval: 15- 
33). Delta(9)-Tetrahydrocannabinol inhibited tumour-cell proliferation in 
vitro and decreased tumour-cell Ki67 immunostaining when administered 
to two patients.
Guzman, M., Duarte, M. J., 
Blazquez, C., Ravina, J. and 
others. (2006). A pilot clinical 
study
of
Delta9- 
tetrahydrocannabinol in patients 
with 
recurrent 
glioblastoma 
multiforme. Br.J.Cancer. 95: 197-
203.
Olfaction
15 subjects
20 mg oral THC
Olfactory thresholds were increased and odour discrimination performance 
was reduced.
Walter C, Oertel BG, Ludyga D, 
Ultsch A, Hummel T, Lötsch J. 
(2014) Effects of 20 mg oral Δ(9) - 
tetrahydrocannabinol 
on 
the 
olfactory 
function 
of 
healthy 
volunteers. Br J Clin Pharmacol. 
78(5):961-9


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Page 148 of 161
Management   of   cannabis 
withdrawal
A volunteer sample 
of 
49 
dependent 
cannabis users
Cannabis
Cannabis Withdrawal Scale has excellent psychometric properties. 
Nightmares and/or strange dreams was the most valid item (Wald 
χ²=105.6, P<0.0001), but caused relatively little associated distress (Wald 
χ²=25.11, P=0.03). Angry outbursts were considered intense (Wald 
χ²=73.69, P<0.0001) and caused much associated distress (Wald χ²=45.54, 
P<0.0001). Trouble getting to sleep was also an intense withdrawal 
symptom (Wald χ²=42.31, P<0.0001) and caused significant associated 
distress (Wald χ²=47.76, P<0.0001).
Allsop, D. J., Norberg, M. M., 
Copeland, J., Fu, S. and others. 
(2011). The Cannabis Withdrawal 
Scale development: patterns and 
predictors of cannabis withdrawal 
and 
distress. 
Drug 
Alcohol 
Depend. 119: 123-129
Cannabis    dependence    or 
withdrawal
51 
DSM-IV-TR 
cannabis-dependent 
treatment seekers
86.4
mg
of
Δ9- 
tetrahydrocannabinol 
and
80
mg
of 
cannabidiol)    (Sativex) 
or placebo
Nabiximols treatment significantly reduced the overall severity of 
cannabis withdrawal relative to placebo (F8,377.97 = 2.39; P = .01), 
including effects on withdrawal-related irritability, depression, and 
cannabis cravings. Nabiximols had a more limited, but still positive, 
therapeutic benefit on sleep disturbance, anxiety, appetite loss, physical 
symptoms, and restlessness.
Allsop DJ, Copeland J, Lintzeris 
N, Dunlop AJ, Montebello M, 
Sadler C, Rivas GR, Holland RM, 
Muhleisen P, Norberg MM,Booth 
J, 
McGregor 
IS. 
(2014) 
Nabiximols 
as 
an 
agonist 
replacement 
therapy 
during 
cannabis 
withdrawal: 
a 
randomized clinical trial. JAMA 
Psychiatry. 71(3):281-91


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Page 149 of 161
Cannabis    dependence    or 
withdrawal
7 cannabis users
Ascending 
order 
in 
15 mg increments across 
separate sessions, up to a 
maximum of 90 mg oral 
THC
Considerable variability in Cmax and tmax was observed. Doses of oral 
Δ(9) -THC larger than those tested previously can be administered to 
individuals with a history of cannabis use, although given the 
pharmacokinetic variability of oral Δ(9) -THC and individual differences 
in sensitivity, individualized dose adjustment is needed to avoid side 
effects and maximize therapeutic response.
Lile JA, Kelly TH, Charnigo RJ, 
Stinchcomb AL, Hays LR (2013) 
Pharmacokinetic
and 
pharmacodynamic 
profile 
of 
supratherapeutic oral doses of Δ(9)
-THC in cannabis users. J Clin 
Pharmacol. 53(7):680-90
Cannabis    dependence    or 
withdrawal
One
20-year-old 
woman
who 
developed 
protracted nausea 
and
vomiting 
secondary
to 
cannabis withdrawal
Nabilone
The patient was successfully treated with nabilone.
Lam PW, Frost DW (2015) 
Nabilone therapy for cannabis 
withdrawal 
presenting 
as 
protracted nausea and vomiting. 
BMJ Case Rep. 2014 Sep 22; 2014


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Page 150 of 161
Cannabis    dependence    or 
withdrawal
Nontreatment- 
seeking    marijuana 
smokers (8 men and 
3 women)
Nabilone, different dose 
(0, 6, 8 mg/day)
Both nabilone dose conditions decreased marijuana relapse and reversed 
withdrawal-related irritability and disruptions in sleep and food intake 
(p<0.05). Nabilone (8 mg/day) modestly worsened psychomotor task 
performance. Neither dose condition increased ratings of capsule 'liking' 
or desire to take the capsules relative to placebo.
Haney M, Cooper ZD, Bedi G, 
Vosburg SK, Comer SD, Foltin 
RW (2013) Nabilone decreases 
marijuana 
withdrawal 
and 
a 
laboratory measure of marijuana 
relapse.
Neuropsychopharmacology. 
38(8):1557-65
Dronabinol   Treatment   for 
Marijuana Addiction
156
Dronabinol: 20mg bid 
for a daily maximum 
dose of 40mg vs Placebo
Although both groups showed a reduction in marijuana use over time, there 
were no differences between the groups. Treatment retention was 
significantly higher at the end of the maintenance phase on dronabinol 
(77%), compared to placebo (61%) (P=.02), and withdrawal symptoms 
were significantly lower on dronabinol than placebo (P=.02).
Levin FR, Mariani JJ, Brooks DJ, 
Pavlicova M, Cheng W, Nunes EV 
(2011) 
Dronabinol 
for 
the 
treatment of cannabis dependence: 
a 
randomized, 
double-blind, 
placebo-controlled 
trial 
Drug 
Alcohol Depend. 116(1-3):142-50


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Page 151 of 161
Smoking
topography 
characteristics 
of 
heavy 
cannabis users
20
Cannabis
Smoking characteristics generally were not significantly associated with 
cognitive performance. Smoking topographymeasures were significantly 
correlated with self-reported measures of cannabis use, indicating validity 
of these assessments, but topography measures were more sensitive than 
self-report in predicting cannabis-related outcomes.
McClure, E. A., Stitzer, M. L., and 
Vandrey,
R.
(2012).
Characterizing
smoking 
topography of cannabis in heavy 
users.
Psychopharmacology 
(Berl). 220: 309-318.
Clinical  and  forensic  drug 
testing.    Oral   fluid    (OF) 
cannabinoid 
pharmacokinetics during ad 
libitum smoking
11 cannabis smokers 
resided in a closed 
research 
unit 
for 
51 days
5-day
oral
delta-9- 
tetrahydrocannabinol 
(THC) treatments
Cannabinoid disposition in OF was highly influenced by Δtime and 
composition of smoked cannabis. Furthermore, cannabinoid OF 
concentrations increased over ad libitum smoking days, in parallel with 
increased cannabis self-administration, possibly reflecting development of 
increased cannabis tolerance.
Lee D, Vandrey R, Mendu DR, 
Murray JA, Barnes AJ, Huestis 
MA 
(2015) 
Oral 
fluid 
cannabinoids in chronic frequent 
cannabis 
smokers 
during 
ad 
libitum cannabis smoking. Drug 
Test         Anal.         7(6):494-501
Lee D, Vandrey R, Milman G, 
Bergamaschi 
M, 
Mendu DR, 
Murray JA, Barnes AJ, Huestis 
MA. (2013) Oral fluid/plasma 
cannabinoid 
ratios 
following 
controlled oral THC and smoked 
cannabis 
administration. 
Anal 
Bioanal Chem. 405(23):7269-79


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Page 152 of 161
THC AEs
Recreational    users 
(N = 24)
Cannabis cigarettes with 
four 
doses 
of 
THC 
(placebo 29, 49 and 69 
mg of THC)
A cubic relationship was observed between 'feeling the drug' and 'wanting 
more'. The THC-induced decrease in 'feeling stimulated' and increase in 
anxiety lasted up to 8 h post-smoking. Sedation at 8 h post-smoking was 
increased by a factor of 5.7 with the highest THC dose, compared to the 
placebo.
Hunault CC, Böcker KB, Stellato 
RK, Kenemans JL, de Vries I, 
Meulenbelt 
J. 
(2014) 
Acute 
subjective effects after smoking 
joints containing up to 69 mg Δ9- 
tetrahydrocannabinol
in 
recreational users: a randomized, 
crossover 
clinical 
trial. 
Psychopharmacology 
(Berl). 
Dec;231(24):4723-33
Synthetic cannabinoid (SC) 
AEs
Respondents (N = 
42;
88%
participation 
rate) 
were 
primarily 
young adults, male, 
racially diverse, and 
high
school 
graduates.
Synthetic 
cannabinoid 
(SC) smoking, despite a 
federal 
ban 
on 
5 
common 
SCs, 
which 
went 
into 
effect 
on 
March 1, 2011
Common reasons reported for use included, but were not limited to, 
seeking a new "high" similar to that produced by marijuana and avoiding 
drug use detection via a positive urine screen. The primary side effects 
were trouble thinking clearly, headache, dry mouth, and anxiety. No 
significant differences were found between synthetic cannabinoid product 
users (ever or current) and nonusers by demographics or other 
characteristics.
Gunderson EW1, Haughey HM, 
Ait-Daoud N, Joshi AS, Hart CL. 
(2014) A survey of synthetic 
cannabinoid 
consumption 
by 
current 
cannabis 
users. 
Subst 
Abus. 35(2):184-9


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Page 153 of 161
THC
AEs
(brain 
morphometry)
MRI scans on young 
adult 
recreational 
marijuana users
Recreational marijuana
Gray matter density analyses revealed greater gray matter density in 
marijuana users than in control participants in the left nucleus accumbens 
extending to subcallosal cortex, hypothalamus, sublenticular extended 
amygdala, and left amygdala, even after controlling for age, sex, alcohol 
use, and cigarette smoking. Trend-level effects were observed for a volume 
increase in the left nucleus accumbens only. Significant shape differences 
were detected in the left nucleus accumbens and right amygdala.
Gilman JM, Kuster JK, Lee S, Lee 
MJ, Kim BW, Makris N, van der 
Kouwe A, Blood AJ, Breiter HC. 
(2014) 
Cannabis 
use 
is 
quantitatively 
associated 
with 
nucleus accumbens and amygdala 
abnormalities 
in 
young 
adult 
recreational users. J Neurosci. 
34(16):5529-38
THC
AEs
on 
neuropsychological 
functions
Heavy 
cannabis 
users, who had a 
history of cocaine 
use (n = 61)
Single doses of cocaine 
HCl (300 mg), cannabis 
(THC μg·kg(-1) ) and 
placebo
Single doses of cannabis impaired psychomotor function and increased 
response errors during impulsivity tasks. Single doses of cocaine improved 
psychomotor function and decreased response time in impulsivity tasks, 
but increased errors.
van 
Wel 
JH, 
Kuypers 
KP, 
Theunissen EL, Toennes SW, 
Spronk 
DB, 
Verkes 
RJ, 
Ramaekers JG (2013)  Single 
doses 
of 
THC 
and 
cocaine 
decrease proficiency of impulse 
control in heavy cannabis users. Br 
J Pharmacol. 170(7):1410-20


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Page 154 of 161
Cannabinoid levels in serum 
or urine in abstinent chronic 
cannabis users.
6 
chronic, 
daily 
cannabis users (one 
female, five males, 
average age 30.0 
years; BMI 20.8)
Moderate-intensity 
workout   and   a   24-hr 
period
of
food 
deprivation;
analysed 
for
∆9-
tetrahydrocannabinol 
(THC)   and   11-nor-9- 
carboxy-∆9- 
tetrahydrocannabinol 
(THCCOOH)  by liquid 
chromatography-tandem 
mass
spectrometry 
(LCMSMS)
There were no major differences in the measured cannabinoid levels in 
serum or urine before and after physical exercise or food deprivation. We 
conclude that exercise and/or food deprivation are unlikely to cause 
sufficient cannabinoid concentration changes to hamper correct 
interpretations in drug testing programmes.
Westin AA1, Mjønes G, Burchardt 
O, Fuskevåg OM, Slørdal L. 
(2014) Can physical exercise or 
food deprivation cause release of 
fat-stored cannabinoids?  Basic 
Clin 
Pharmacol 
Toxicol. 
115(5):467-71


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Page 155 of 161
Safety and adverse effects of 
coadministration of 
CBD 
and fentanyl
Healthy 
volunteers 
aged 21 to 65 years 
with 
prior opioid 
exposure, regardless 
of the route
CBD, 
coadministered 
with
intravenous 
fentanyl
SAFTEE data were similar between groups without respiratory depression 
or cardiovascular complications during any test session. After low-dose 
CBD, tmax occurred at 3 and 1.5 hours in sessions 1 and 2, respectively. 
After high-dose CBD, tmax occurred at 3 and 4 hours in sessions 1 and 2, 
respectively. Cannabidiol does not exacerbate adverse effects associated 
with intravenous fentanyl administration. Coadministration of CBD and 
opioids was safe and well tolerated.
Manini 
AF, 
Yiannoulos 
G, 
Bergamaschi MM, Hernandez S, 
Olmedo R, Barnes AJ, Winkel G, 
Sinha R, Jutras-Aswad D, Huestis 
MA, Hurd YL (2015) Safety and 
pharmacokinetics 
of 
oral 
cannabidiol when 
administered 
concomitantly with intravenous 
fentanyl in humans. J Addict Med. 
9(3):204-10
Pharmacokinetics in chronic, 
daily cannabis smokers who 
received high-dose oral THC 
pharmacotherapy and later a 
smoked cannabis challenge
11   daily   cannabis 
smokers
0, 30, 60, or 120 mg/d 
THC for four 5-day 
medication sessions
The significant withdrawal effects noted during placebo dronabinol 
administration were supported by significant plasma THC and 11-OH- 
THC concentration decreases. During active dronabinol dosing, significant 
dose-dependent increases in THC and 11-OH-THC concentrations support 
withdrawal symptom suppression.
Milman G, Bergamaschi MM, Lee 
D, 
Mendu 
DR, 
Barnes 
AJ, 
Vandrey R, Huestis MA (2014) 
Plasma
cannabinoid 
concentrations during dronabinol 
pharmacotherapy 
for 
cannabis 
dependence. Ther Drug Monit. 
36(2):218-24


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Page 156 of 161
Drug-drug
interaction 
between cannabidiol (CBD) 
and clobazam (CLB) in 
refractory 
epilepsy 
in 
children
13    subjects    with 
refractory epilepsy
Cannabidiol (CBD) and 
clobazam (CLB)
CLB and CBD are both metabolized in the cytochrome P450 (CYP) 
pathway. Nine of 13 subjects had a >50% decrease in seizures, 
corresponding to a responder rate of 70%. The increased CLB and nCLB 
levels and decreases in seizure frequency occurred even though, over the 
course of CBD treatment, CLB doses were reduced for 10 (77%) of the 13 
subjects. Side effects were reported in 10 (77%) of the 13 subjects, but 
were alleviated with CLB dose reduction
Geffrey AL, Pollack SF, Bruno 
PL, Thiele EA (2015) Drug-drug 
interaction between clobazam and 
cannabidiol 
in 
children 
with 
refractory 
epilepsy. 
Epilepsia. 
2015 Jun 26.


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Appendix 2: Table of Previously Conducted Trials using Palmitoylethanolamide
Indication
&
Trial 
Design
Number of 
Patients
PEA Dosage
Main Results
Ref
Sciatic pain 
Double-blind, 
randomized, two
doses of PEA vs placebo
636
1st arm: 300mg/die 
x 3 weeks
2nd arm: 300mg/bid for 
weeks
Significant decrease of pain on 
VAS (from 7 to 2)
G. Guida, A. de Fabiani, F. Lanaia, A. et al. La palmitoiletanolamida 
(Normast) en el dolor neuropatico cronico por lumbociatalgia
de tipo compresivo: estudio clinico multicentrico. Dolor 2010; 25: 
35-42
Sciatic pain 
Double-blind, 
randomized, two
doses of PEA vs placebo
111
1st arm: 300mg/die 
for 3 weeks
2nd arm: 300mg/bid for 
weeks
Significant decrease in the duration 
of treatment with anti-inflammatory 
and analgesic drugs
Canteri L et al. Reduction of analgesics in patients suffering from 
lumbosciatic pain, treated with palmitoylethanolamide. Dolor 2010; 
25: 227-34.
Pudendal neuralgia
Case Report
1
300mg/tid gradually decreasing 
to 300mg/die
for1 year
Resolution of chronic pelvic pain
Calabrò RS, Gervasi G, Marino S, et al. Misdiagnosed Chronic 
Pelvic Pain: Pudendal Neuralgia Responding to a Novel Use of 
Palmitoylethanolamide. Pain Med 2010; 11(5): 781-4.
Diabetic neuropathic pain
Open
30
300mg/bid for 60 days
Significant reduction of pain, burning, 
paraesthesia and numbness
Schifilliti C, Cucinotta L, Fedele V, et al. Palmitoylethanolamide 
reduces the symptoms of neuropathic pain in diabetic patients. XIV 
Congress of the European Shock Society. September, Taormina, Italy 
2011.
Postoperative
pain 
(surgical extraction
of impacted lower third 
molars)
Single-blind, randomized, 
splitmouth
30
300mg/bid for 6 days 
before and 9 days after 
surgery
Significant reduction in pain intensity
Bacci C, Cassetta G, Emanuele B, et al. Randomized split-mouth 
study on postoperative effects of palmitoylethanolamide for impacted 
lower third molar surgery. ISRN Surg. 2011 2011917350.
TMJ    pain    caused    by 
osteoarthritis
Double blind randomized 
vs
NSAIDs
24
300mg at morning + 
600mg at evening for7 
days; followed by 
300mg/bid for 7 days
Vs ibupfofen (600 mg/tid 
for 14 days)
Significant decrease of pain on 
VAS (from 7 to 0.7) an significant 
better maximum mouth opening 
compared to ibuprofen.
Bortolotti F, Russo M, Bartolucci ML, et al. Palmitoylethanolamide 
versus NSAID in the treatment of TMJ’s pain. J Orofac Pain
Diabetic neuropathy pain 
associated
with
carpal
tunnel 
syndrome
Group-controlled, 
randomized,
PEA treatment v standard 
care
50
600 mg/bid for 60 days
Significant relief of pain.
Significant
improvement
of 
neurophysiologic
parameters
Assini A, Laricchia D, Pizzo R, et al. The carpal tunnel syndrome 
in diabetes: clinical and electrophysiological improvement after 
treatment with palmitoylethanolamide Eur J Neurol 2010; 17(S3): 
295.
Carpal tunnel syndrome in 
diabetic
patients
Group-controlled, 
randomized vs
non-treated patients
40
600mg/bid for 60 days
Significant reduction of pain and 
functional status.
Significant improvement neurophysiologic 
parameters
Assini A, Laricchia D, Pizzo R, et al. Tunnel carpale nel paziente 
diabetico. Migliloramento clinico ed elettrofisiologico dopo trattamento 
con palmitoiletanolamide. [Carpal tunnel syndrome in the
diabetic patient. Clinical and electrophysiologic improvement after 
treatment with palmitoylethanolamide]. 34th National Congress 
AISD – New frontiers in pain medicine. May, Riccione, Italy 2011.
Pain
associated
with 
carpal tunnel
26
1st arm: 300mg/bid for 30 
days
Significant dose-dependent reduction 
of pain and improvement of
Conigliaro R, Drago V, Foster PS, et al. Use of palmitoylethanolamide 
in the entrapment neuropathy of the median in the wrist. Minerva


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syndrome
Group-controlled, 
randomized,
two doses of PEA vs non- 
treated
patients
2nd arm: 600mg/bid for 30 
days
neurophysiologic parameters compared 
with control group.
Med 2011; 102(2): 141-7.
Neuropathic pain
Open
27
300mg/bid for 3 weeks 
followed by 
300mg/die for 4 weeks
Significant reduction of pain and 
improvement of electrophysiological 
parameters
Biasiotta    A,    Di    Stefano    G,    Leone    C,    et    al.    Efficacy    of 
palmitoylethanolamide
in patients with painful neuropathy. A clinical and neurophysiological open 
study. Preliminary results. Eur J Pain
2010; 4(1): 77.
Low back pain
Open
(Combination 
therapy)
20
600mg/bid for 30 days
+
oxycodone
Significant decrease of pain on 
VAS (from 7 to 2.5)
Desio P. Combination of oxycodone and palmitoylethanolamide for 
low back pain treatment. Rivista Siared di Anestesia e Medicina 
Critica 2011; 1(2): 62-71.
Neuropathic chronic pain 
(Diabetic
neuropathy
and 
postherpetic
neuralgia)
Open
(Combination 
therapy)
30
Combination of Pregabalin+
PEA 600mg bid 
for 45 days
+
pregabalin
Significant decrease of pain on 
VAS, from 7.6 to 1.8
Desio P. Associazione tra pregabalin e palmitoiletanolamide per il 
trattamento del dolore neuropatico. [Association of palmitoylethanolamide 
and pregabalin in the management of neuropathic pain].
Pathos 2010; 17(4): 9-14.
Various pain states
Open
(Combination 
therapy)
517
600mg/bid for 3 weeks 
followed by 600mg/die 
for 4 weeks
+
Pregabalin and oxycodone
61% decrease of mean pain score on 
Numeric Rating Scale
Di Paolo A, Gianfelice V, Silvestri C, et al. La palmitoiletanolamide 
nel trattamento del dolore attivato dal sistema gliale: nostra esperienza. 
[Palmitoylethanolamide in the management of gliaactivated
pain. Our experience] 34th National Congress AISD –  
New frontiers in pain medicine. May 2011, Riccione, Italy.
Low back pain
Open
(Combination 
therapy)
Controlled
(PEA
+standard analgesics 
group
vs
standard 
analgesics
only)
81
600mg/bid for 3 weeks 
followed by 
600mg/die for 4 weeks
+/-
Standard analgesics
Significant reduction of pain intensity 
in the PEA group compared to control 
group
Palomba R, Adfiletta S, Candiello A, et al. Multimodal analgesia
for chronic pain: rationale and future directions. Naples Pain Conference. 
Napoli, Italy 2010.
Diabetic neuropathic pain
Group-
controlled:
Combination
of  PEA  +Pregabalin  vs 
Pregabalin
74
600mg/bid for 10 days 
followed by 
600mg/die for 20 days 
followed by 
300mg/die for 30 days
Significantly higher rate of responders 
(i.e., <60% decrease in
pain score) in the combination therapy 
group compared to pregabalin       
only group.
Adiletta    S,    Candiello    A,    Arminio    D,    et    al.    Pregabalin    and 
Palmitoylethanolamide
in diabetic neuropathic pain: an randomized
clinical trial. 34th AISD (Italian Association for the Study of Pain) 
Congress, Riccione, Italy 2011.
Sciatic pain 
Group-controlled, 
randomized,
combination
of
PEA
+standard
analgesic    therapies    vs 
standard
analgesic therapies
85
300mg/bid for 30 days
Significant relief
of pain (scored both on VAS and 
Oswestry Low Back Pain Scale) in 
the PEA group compared to the 
analgesic-only group.
Dominguez CM, Diaz Martin AA, Ferrer FG, et al. Palmitoiletanolamida 
(PEA) en lumbociatica en asociacion al tratamiento habitual. 
[Palmitoylethanolamide in lumbosciatic pain in association with standard 
therapy] 8th National Congress of the Sociedad
Española del Dolor. May Madrid, Spain 2010.
Neuropathic    pain    and 
spasticity in
post-stroke patients
20
600mg/bid for 60 days 
followed by 
600mg/die for 30 days
Significant decrease of pain and 
spasticity
Russo G, Parabita M. Decrease of spasticity and pain after stroke 
due to treatment with PEA. 14th congress European Shock Soc, 
Taormina, Italy 2011.


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Open,  controlled  PEA  + 
Physiother()
vs group treated with only 
Physiother)
Neuropathic
pain 
associated with
multiple sclerosis
Open
20
300mg/bid for 60 days
Significant decrease of neuropathic 
pain
Mancardi GL, Infante MT, Capello E, et al. Palmitoylethanolamide 
relieves neuropathic pain associated to multiple sclerosis. XL National 
Congress of the Italian Neurological Society. Padova, Italy
2009.
Chronic
pelvic
pain 
associated
with
endometriosis/ 
dysmenorrhoea
/interstitial cystitis
Open
25
200mg/tid (+polydatin 
20mg/tid) for 40 days
Significant reduction of pain on 
VAS (from 6.8 to 1.7).
Significant decrease in the use of 
NSAIDs.
Palomba   R,    De   Simone   MG,   GIovannini    A,    et   al.    Use   of 
palmitotlethanolamide
(PEA) + polydatin in the chronic pelvic pain. 
SIAARTI, October 2010, Parma, Italy.
Adolescent
primary 
dysmenorrhoea
Open
20
400mg/bid (+ polydatin 
40mg/bid)
for 6 months
70% decrease of pelvic pain
Fulghesu A, Magnini R , Mazzella S, et al. Treatment of adolescent 
dysmenorrhea by a new inhibitor of mast cells-induced inflammation 
(palmitoylethanolamide + trans polydatin). 16th Congress of 
Pediatric and Adolescent Gynecology, May Montpellier, France 
2010.
Chronic  pelvic  pain  and 
dyspareunia
associated
with 
endometriosis
Open (case series)
4
200mg/bid (+ polydatin 
20mg/bid) for 3 months
Significant decrease of pelvic pain. 
Significant decrease of dyspareunia. 
Significant reduction in the use of 
analgesics.
Indraccolo U, Barbieri F. Effect of palmitoylethanolamidepolydatin 
combination on chronic pelvic pain associated with endometriosis: 
preliminary observations. Eur J Obstet Gynecol Reprod
Biol 2010; 150(1): 76-9.
Chronic
pelvic
pain 
associated
with endometriosis
Double
blind,
,randomized parallel- 
group, placebo-controlled
61
400mg/tid (+ 40mg/tid 
polydatin) for
3 months 
Vs
celecoxib 200 mg/bid for 
7 consecutive days
Significant decrease of cronic pelvic 
pain, dysmenorrhoea and dyspareunia 
in the PEA group compared to 
placebo group
Cobellis L, Castaldi MA, Giordano V, et al. Effectiveness of the 
association micronized N-Palmitoylethanolamine (PEA)-
transpolydatin   in   the   treatment   of   chronic   pelvic   pain   related   to 
endometriosis
after laparoscopic assessment: a pilot study. Eur J Obstet 
Gynecol Reprod Biol 2011; 158: 82-6.
Safety and Efficacy Study 
of PEA and Polydatin on 
Intestinal 
Inflammation 
and Visceral Hyperalgesia 
in IBS Patients. Phase II 
clinical study by CM&D 
Pharma Limited/Nestle
Recruitment 
status
is 
Recruiting
200
mg
Micronised 
Palmitoylethanolamide (PEA)  and 
20 mg Polydatin
-
http://clinicaltrials.gov/ct2/show/NCT01370720
Whether
the
anti- 
inflammatory
agent 
palmitoylethanolamide 
(PEA) can counteract the 
increase    of    intraocular 
pressure  (IOP)  that  may 
occur  after  neodymium- 
doped: yttrium aluminum 
garnet   (Nd:YAG)   laser 
iridotomy
15
after 
bilateral laser 
iridotomy 
(Visulas 
YAG
III
Laser; Zeiss) 
for
the
prevention of 
primary 
closed-angle 
glaucoma.
Pretreatment  with  placebo  or  PEA 
(t0)
Visimast 300 mg, Epitech Group Srl
PEA can counteract the increase of IOP that 
occurs after iridotomy. It is likely that PEA 
controls the inflammatory process after 
iridotomy.
Pescosolido 
N, 
Librando 
A, 
Puzzono 
M, 
Nebbioso 
M. 
Palmitoylethanolamide effects on intraocular pressure after Nd:YAG laser 
iridotomy: an experimental clinical study. J Ocul Pharmacol Ther. 2011 
Dec;27(6):629-35.
Oral
palmitoyl- 
ethanolamide   (PEA)   on
42
PEA 300-mg/bid 
Vs
Systemic administration of PEA reduces IOP 
in   patients   with   glaucoma   and   ocular
Gagliano  C,  Ortisi  E,  Pulvirenti  L,  Reibaldi  M,  Scollo  D,  Amato  R, 
Avitabile  T,  Longo  A.  Ocular  hypotensive  effect  of  oral  palmitoyl-


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intraocular pressure (IOP) 
in primary open angle 
glaucoma (POAG) and 
ocular hypertension (OH). 
Randomized, 
double- 
blind, crossover clinical 
trial
placebo (PEA vehicle tablets bid)
hypertension. PEA could be a valuable tool 
for the treatment of glaucoma
ethanolamide:  a  clinical  trial.  Invest  Ophthalmol  Vis  Sci.  2011  Aug 
3;52(9):6096-100.
Vulvodynia
and 
proctodynia.
Case Study
1
baclofen
5
%
and 
palmitoylethanolamide 400 mg, tid
Topical baclofen and palmitoylethanolamide 
can be a viable treatment option in chronic 
vulvodynia and proctodynia.
Keppel Hesselink JM, Kopsky DJ, Sajben NL. Vulvodynia and proctodynia 
treated with topical baclofen 5 % and palmitoylethanolamide. Arch Gynecol 
Obstet. 2014 Aug;290(2):389-93.
Chronic    regional    pain 
syndrome (CRPS) 
intractable CRPS
type 1
Case study
1
PeaPure® 400 mg capsules
(JP Russell Sciences Ltd, Nicosia, 
Cyprus) and topical 10% ketamine 
cream
The combination of palmitoylethanolamide 
and ketamine 10% cream reduced pain by 
more than 50% after 1 month of treatment, 
and a marked reduction in swelling and skin 
discoloration was noticed.
Keppel Hesselink JM, Kopsky DJ Treatment of chronic regional pain 
syndrome
type 1 with palmitoylethanolamide and topical
ketamine cream: modulation of nonneuronal cells. J Pain Res 2013 Mar 239- 
45
Atopic Dermatitis
Investigator-blinded,
split-body, 
randomized 
trial of children and adults 
with atopic dermatitis.
43
PEA-containing nonsteroidal cream 
in combination with the designated 
midpotency 
topical 
corticosteroid 
twice daily.
PEA-containing 
nonsteroidal 
cream 
demonstrated more rapid clearance than the 
sides treated twice daily with a topical 
corticosteroid 
in 
combination 
with 
a 
designated moisturizer cream.
James Q. Del Rosso Use of a Palmitoylethanolamide- Containing 
Nonsteroidal Cream for Treating Atopic Dermatitis: Impact on the  
Duration of Response and Time Between Flares Cosmetic Dermatology® • 
APRIL 2007 • VOL. 20 NO. 4
Long-term    management 
of atopic eczema
Multinational, 
multicentre, observational,
non- 
controlled,
prospective 
cohort study
2456
Unique  lamellar  matrix  containing 
N-palmitoylethanolamine (PEA)
Substantial relief of objective and subjective 
symptoms of atopic eczema after regular 
skin care with the study cream. The patient- 
related effectiveness (decline of pruritus and 
loss of sleep) indicated a gain in quality of 
life in these patients. The reduced use of 
topical corticosteroids is important in view 
of 
safety 
and 
pharmacoeconomic 
implications in the treatment of atopic 
eczema.
Eberlein B, Eicke C, Reinhardt HW, Ring J. Adjuvant treatment of atopic 
eczema: assessment of an emollient containing N-palmitoylethanolamine 
(ATOPA study). J Eur Acad Dermatol Venereol. 2008 Jan;22(1):73-82.
to          compare          the
supplementation        with
Sinerga         with         the
supplementation 
with 
bacterial extracts, for the 
effect on the frequency of 
episodes 
of 
respiratory 
infection that had resulted 
in 
a 
prescription 
for 
antibiotics.
167 children,
aged  3  to  7 
years, of both 
sexes, with a 
clinical 
history
of 
recurrent 
respiratory 
infections
Sinerga 
a 
nutritional 
product 
containing 
palmitoylethanolamide, 
bovine colostrum, phenylethylamine 
and the new generation of probiotic 
kluyveromyces FM B0399
The results showed a greater reduction in the 
frequency of respiratory infections with 
antibiotic therapy in the group of children 
supplemented with Sinerga than in the group 
treated with bacterial extracts. In particular, 
it was observed that 49.3% of the children 
supplemented with Sinerga, against 5% of 
those supplemented with extracts, had no 
infectious 
episodes 
requiring 
the 
administration of an antibiotic. 100% of 
subjects supplemented with Sinerga have 
had no more than two episodes of respiratory 
infection, while this condition, in the cohort 
treated with bacterial extracts, was observed 
in only 51% of cases.
Nigro A, Nicastro A, Trodella R. Retrospective observational study to 
investigate Sinerga, a multifactorial nutritional product, and bacterial 
extracts in the prevention of recurrent respiratory infections in children. Int 
J Immunopathol Pharmacol. 2014 Jul-Sep;27(3):455-60
To 
determine 
whether 
changes in seminal plasma 
concentrations     of     the
90
men 
attending an 
infertility
Palmitoylethanolamide 
and 
OEA 
extracted from seminal plasma were 
quantified by ultra high-performance
Palmitoylethanolamide 
and 
OEA 
concentrations in seminal plasma were lower 
in    men    with    asthenozoospermia    and
Amoako AA, Marczylo TH, Elson J, Taylor AH, Willets JM4, Konje JC. 
Relationship  between  seminal  plasma  levels  of  anandamide  congeners


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endogenous
lipid
signaling
molecules 
palmitoylethanolamide 
(PEA)
and
oleoylethanolamide 
(OEA)   have   significant 
effects on sperm quality
clinic
for 
semen 
analysis.
liquid    chromatography    (HPLC)- 
tandem mass spectrometry
oligoasthenoteratozospermia compared with 
men 
with 
normal 
semen 
parameters. 
Palmitoylethanolamide and OEA rapidly 
and significantly improved sperm motility 
and maintained viability without affecting 
mitochondria activity in vitro.
palmitoylethanolamide and oleoylethanolamide and semen quality. Fertil 
Steril. 2014 Sep 8. pii: S0015-0282(14)01394-6