Effect of Cannabis Administration and Endocannabinoids on HIV Neuropathic Pain Primary Study - Phase 2
Phase: PHASE2
Conditions: Cannabis, HIV Neuropathy, Pain Syndrome
Sponsor: University of California, San Diego

 
 
 
 
 
 
Study Protocol and Statistical Analysis Plan 
 
Title of Study: Effect of Cannabis and Endocannabinoids on HIV Neuropathic Pain 
 
NCT: NCT03099005 
 
Date of Document: 6-12-2019 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 

 
2 
 
 
CONTENTS 
 
 
Page 
 
GLOSSARY OF PROTOCOL-SPECIFIC TERMS ........................................................................ 3 
ABSTRACT ..................................................................................................................................... 4 
SCHEMA ....................................................................................................................................... 5 
1.0 
INTRODUCTION ............................................................................................................... 6 
1.1 
Background ........................................................................................................... 6 
2.0 
STUDY DESIGN ............................................................................................................... 8 
3.0 
SELECTION AND ENROLLMENT OF PARTICIPANTS ................................................... 8 
3.1 
Inclusion Criteria .................................................................................................... 8 
3.2 
Exclusion Criteria .................................................................................................. 9 
4.0 
STUDY TREATMENT ....................................................................................................... 9 
4.1 
NIDA Drug Supply Provision of Cannabis Product ................................................ 9 
4.2 
Cannabis Administration Protocol ....................................................................... 10 
            4.3 
Individual Monitoring of Pain and Cannabis Taken (IMPACT)………….......……11 
5.0 
CLINICAL MANAGEMENT ISSUES ............................................................................... 11 
5.1 
Adverse Events ................................................................................................... 11 
5.2 
Toxicity ................................................................................................................ 12 
5.3 
Monitoring Participant Safety .............................................................................. 13 
6.0 
CRITERIA FOR DISCONTINUATION............................................................................. 13 
6.1 
Criteria for Discontinuation of Cannabis Administration ...................................... 13 
6.2 
Premature Study Discontinuation ........................................................................ 14 
7.0 
STATISTICAL ANALYSIS PLAN .................................................................................... 14 
7.1 
Aim 1 Measures and Analyses ............................................................................ 14 
7.2 
Aim 2 Measures and Analyses ............................................................................ 15 
7.3 
Aim 3 Measures and Analyses ............................................................................ 16 
7.4 
Power Analyses ................................................................................................... 16 
8.0 
PARTICIPANTS .............................................................................................................. 17 
 
8.1       Monitoring………………………………………………………………………………17 
8.2 
Institutional Review Board (IRB) Review and Informed Consent ........................ 18 
8.3 
Participant Confidentiality .................................................................................... 18 
8.4 
Study Discontinuation .......................................................................................... 18 
9.0 
REFERENCES ................................................................................................................ 19 

 
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GLOSSARY OF PROTOCOL-SPECIFIC TERMS 
 
2AG: 2-arachidonoylglycerol 
AE: adverse event 
AEA: N-arachidonoylethanolamine 
ARCI: Addiction Research Center Inventory 
CBD: cannabidiol 
CMCR: Center for Medicinal Cannabis Research 
DEA: Drug Enforcement Administration 
EC: endocannabinoid 
EMA: Ecological momentary assessment 
FAAH: fatty acid amide hydrolase 
FDA: Food and Drug Administration 
HAND: HIV-associated neurocognitive disorders 
HIV-NP: HIV-associated neuropathic pain 
HIV-SN: HIV sensory neuropathy 
HNRP: HIV Neurobehavioral Research Program 
HRV: heart rate variability 
IMPACT: Individual Monitoring of Pain and Cannabis Taken  
LC/MS: liquid chromatography-tandem mass spectrometry 
MAGL: monoacylglycerol lipase 
METH: methamphetamine 
NNT: the number needed to treat 
NP: neuropathic pain 
NPRS: Numeric Pain Rating Scale 
PBMC: peripheral blood mononuclear cells 
PGIC: Patient Global Impression of Change 
PLWH: persons living with HIV 
SAE: serious adverse event 
SMS: short message service 
SUI: Substance Use Interview 
THC: delta-9-tetrahydrocannabinol 
TNFα: tumor necrosis factor alpha 
TNS: Total Neuropathy Score 
VAS: Visual Analog Scale 
 
 
 

 
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ABSTRACT 
 
HIV-associated neuropathic pain (HIV-NP) affects a significant proportion of people living with 
HIV (PLWH) and has a major impact on everyday functioning and quality of life in this 
population. Over the past decade a growing number of preclinical studies and clinical trials have 
indicated that cannabis administration and manipulation of the endocannabinoid (EC) system 
may have therapeutic utility in addressing HIV-NP. EC CB2 receptor activation and inhibition of 
the EC deactivation enzymes fatty acid amide hydrolase (FAAH) and monoacyglycerol lipase 
(MAGL) have been shown to decrease pain in rodent models of HIV-NP, while acute exposure 
to cannabis reduces self-reported pain in PLWH with neuropathy. However, little work has been 
conducted to elucidate the effects of the two primary cannabinoids (delta-9-
tetrahydrocannabinol, THC and cannabidiol, CBD) on the EC system or to assess EC function 
in PLWH. The objective of this application is to address these fundamental gaps in our 
knowledge by: 1) examining the acute effect of administering NIDA-prepared THC/CBD 
products on HIV-NP; 2) utilizing mHealth text messaging to monitor daily real-world self-
administered cannabis effects on pain; 3) assessing the relationship between cannabinoids and 
EC biomarkers, including ligands, enzymes, and receptor expression; and 4) conducting 
exploratory analyses to evaluate the effect of longitudinal cannabinoid use on changes in HIV-
NP over time. We will examine the effect of low (0.01%), medium (one vial of 5.1%), and high 
dose (two vials of 5.1%) CBD-containing cannabis on NP, the EC system, and heart rate 
variability (as a proposed objective biological measure of pain) in 100 PLWH who use cannabis 
to treat neuropathic pain. We will subsequently employ a mobile phone text messaging system, 
the Individual Monitoring of Pain And Cannabis Taken (IMPACT), to track cannabis exposure, 
CBD and THC consumption, and pain over a period of 6 months in these same PLWH 
participants. IMPACT will be used quantify the real-time effects of acute CBD/THC exposure on 
pain before and after cannabis self-administration, the real-time relationship between self-
reported pain and changes in HRV, and to assess any longitudinal changes in NP, HIV clinical 
outcomes (viral load, CD4) and cognition during the 6-month period. This plan allows us to 
acquire data and compare the effects of cannabis product obtained from NIDA and self-
administered cannabis obtained from local medicinal dispensaries. The overarching hypothesis 
is that CBD exposure and a higher CBD/THC ratio will exert beneficial effects both in the 
laboratory and during the observational study, including increasing EC biomarkers and reducing 
NP. In summary, this approach will advance our understanding about several key issues, 
including the interaction between cannabis constituents, the EC system and pain, the biological 
mechanisms that underlie these effects (EC enzymes, receptor), and the longer-term effects of 
cannabis use on health-related outcomes in HIV, including predictors of mortality (HRV, CD4, 
viral load) and neurocognition. 

 
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SCHEMA 
 
Effect of Cannabis Administration and Endocannabinoids on HIV Neuropathic Pain 
 
 
DESIGN: Our objective is to assess PLWH who have neuropathic pain and are currently using 
cannabis, including light use (1-4 times per month) and heavy use (5+ times per month). These 
participants will be enrolled in a study that consists of two stages: Stage 1) PLWH will 
participate in a 6-month mHealth text messaging program (Individual Monitoring of Pain and 
Cannabis Taken, or IMPACT) that will examine the association between cannabis obtained from 
local dispensaries and changes in daily pain. Participants will return for a visit after 6 months for 
follow-up testing so we can examine longitudinal changes in neuropathic pain, 
neuropsychological performance and EC function. Stage 2) A double blind crossover study 
where we administer three different doses of vaporized cannabis to each participant that contain 
THC and varying concentrations of CBD (low, medium, high), including: a) 2 vials of 0.01% CBD 
+ 1.9% THC, b) 1 vial of 0.01% CBD + 1.9% THC and 1 vial of 5.1% CBD + 1.4% THC, and c) 2 
vials of 5.1% CBD + 1.4% THC. Here we will examine the acute effects of cannabis obtained 
from NIDA on pain intensity, blood endocannabinoid (EC) levels, and the relationship of pain 
with heart rate variability (HRV). 
 
POPULATION: PLWH with neuropathic pain and current cannabis use.  
 
STRATIFICATION: none 
 
REGIMEN OR INTERVENTION  
Three doses of cannabis (with varying concentrations of CBD) administered once per day on 
three separate days. 
 
 
 
 
 
 
 
 
 
 
 
 
 
 

 
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1.0 
INTRODUCTION 
 
HIV-associated neuropathic pain (HIV-NP) affects a significant proportion of people living with 
HIV (PLWH) and is one of the leading causes of disability in this population. Acute cannabis 
administration is reported to alleviate HIV-NP, but we have limited knowledge about the effects 
of cannabis constituents (THC and cannabidiol/CBD), the consequences of long-term cannabis 
use, and the impact of cannabis on endocannabinoid (EC) function in PLWH. Our objective is to 
address these three fundamental gaps in our knowledge by: 1) examining the acute effects of 
various CBD/THC products on HIV-NP, 2) utilizing a mHealth text messaging protocol 
(Individual Monitoring of Pain and Cannabis Taken or IMPACT) to monitor daily real-world 
cannabis use and changes in pain; 3) studying the relationship between cannabinoids, EC 
biomarkers, and chronic neuropathic pain. 
 
1.1 
Background 
 
HIV-related neuropathic pain (HIV-NP) represents a significant problem for PLWH. HIV sensory 
neuropathy (HIV-SN), typically characterized by sensory deficits, numbness, tingling, or pain in 
feet or hands, is a common health concern in people living with HIV (PLWH)1. HIV-SN is often 
associated with neuropathic pain (NP) described as “stabbing”, “burning” or “aching” that is the 
most frequent source of HIV-SN disability2, while the prevalence of reported pain in PLWH 
ranges from 27 to 97%3. A large scale study by our group indicated that 57% (881 out of 1539 
PLWH) exhibited HIV-SN and 38% reported HIV-NP4. Treatment of HIV-NP remains difficult; a 
2010 review indicated that only capsaicin, human nerve growth factor, and smoked cannabis 
showed superior pain reduction compared to placebo5. Studies at the University of California 
Center for Medicinal Cannabis Research (CMCR) indicate that 34-40% of patients exposed to 
cannabis cigarettes with delta-9-tetrahydrocannabinol (THC) exhibited significant pain reduction 
compared to 17-20% on placebo6-8. While THC doses in the 1.3% to 3.5% range alleviate pain 
for some participants, higher doses of THC (7-8%) did not provide additional benefit for pain 
reduction8 or actually increased capsaicin-induced pain in healthy volunteers9. Importantly, 
combined cannabidiol (CBD)/THC extracts are reported to be more effective at treating pain 
compared to THC alone in human cancer-related pain and in rodents10, 11. CBD exhibits 
antioxidant and neuroprotective properties, inhibiting the release of inflammatory cytokines such 
as TNFα12. However, the optimal THC/CBD ratio for effective pain treatment is not yet known. 
There may also be discrepancies between data obtained from controlled clinical trials and the 
use of unregulated cannabis obtained from dispensaries. There is thus a clear need to close the 
gap between existing clinical data and real-life cannabis use from public sources, including the 
effects on the endocannabinoid (EC) system and NP. 
 
Endocannabinoids reduce pain and modulate neuronal activity at synapses throughout pain 
processing pathways, but the effect of cannabis on the EC system is understudied 13. The EC 
system includes two receptors, CB1 and CB2, and two primary ligands, N-
arachidonoylethanolamine (AEA) and 2-arachidonoylglycerol (2-AG), which are deactivated by 
the enzymes fatty acid amide hydrolase (FAAH) and monoacylglycerol lipase (MAGL), 
respectively14, 15. EC ligands act as a negative feedback system that inhibits the release of pro-
inflammatory cytokines and reduces neuronal signaling in response to pain13, 15, 16. Elevated 

 
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peripheral levels of AEA and 2-AG occur in preclinical pain models13 and FAAH and MAGL 
inhibitors produce antinociceptive effects in rodent models of acute and chronic pain17, 18. Mice 
lacking CB2 receptors also show enhanced pain responses to sciatic nerve ligation19. Despite 
the reported benefits of acute cannabis treatment for pain, chronic cannabis use may disrupt EC 
function20. Heavy cannabis use (several days per week) reduces EC ligand levels21 and CB1 
and CB2 expression in both humans and mice22-25. Psychotic patients with heavy cannabis use 
exhibited decreased CB2 and increased FAAH in peripheral blood mononuclear cells (PBMC) 
compared to healthy controls22, while increased AEA in cannabis-naïve schizophrenia patients 
was completely blocked by cannabis use20. Cannabis use may disrupt EC function, but little is 
known about the specific effects of THC and CBD. One study in schizophrenia patients reported 
that 4 weeks of administered CBD increased plasma AEA and reduced FAAH26. Preclinical and 
in vitro data show that CBD may increase AEA expression by inhibiting both neuronal uptake 
and FAAH activity27. In contrast, THC, but not CBD, is a strong CB1 and CB2 receptor agonist28, 
29 and could represent the primary cannabis constituent that disrupts EC function. Overall, these 
data suggest that THC and CBD may have differential effects on EC activity, a question that 
requires investigation in a real-world setting of chronic cannabis use. 
 
Pain is typically assessed by self-report, but the field would benefit from the use of biological 
measures sensitive to HIV-NP. Common pain measures include the Visual Analog Scale (VAS), 
where individuals mark their level of pain on a 10 cm line from “no pain” to “worst pain” and the 
Numeric Pain Rating Scale (NPRS), a 0-10 scale with similar endpoints5. In contrast to self-
report, suggested metrics of objective pain such as fMRI neuroimaging remain in 
development30. Another proposed option, heart rate variability (HRV), is a measure of 
autonomic function closely related to pain self-report and analgesic efficacy31-34. HRV quantifies 
the beat-to-beat variation in heart rate and provides a measure of sympathetic and 
parasympathetic tone. Healthy individuals exhibit higher HRV, but HRV is significantly lower in 
PLWH35-37, correlates with the level of pain intensity in chronic fibromyalgia38, and improved 
HRV after biofeedback is associated with less pain on VAS39. Persons with effective analgesic 
treatment of chronic pain exhibited improved HRV relative to pain sufferers with ineffective 
treatment32, suggesting HRV may serve as a pain biomarker.  
 
The effects of cannabis on health outcomes and cognition in HIV remain unclear. Despite 
prevalent cannabis use, there are significant concerns that drug exposure may impair cognition 
and affect everyday functioning40-42. Chronic cannabis use is associated with cognitive deficits 
across a wide range of domains (memory, attention, executive function)43-45, but little is known 
about the potential neuropathology46. Preclinical studies indicate that CBD may have beneficial 
effects on cognition, including rescuing memory impairment in a mouse model of malaria47, 
improving object recognition in a model of Alzheimer’s disease48, and attenuating visuospatial 
deficits induced by THC in rhesus monkeys49, but CBD exposure effects in PLWH are not 
known. Similarly, the effects of CBD and THC on measures of disease state, such as CD4 level 
and viral load, are not well understood. Rhesus macaques exposed to THC for 6 months 
exhibited lower viral load after infection with simian immunodeficiency virus50, while daily 
cannabis use was associated with lower viral load among recently seroconverted PLWH when 
compared to less frequent use51. However, THC and CBD exposure was not reported in this 
study and remains an important and understudied issue in this field. 
 
mHealth text messaging will serve as a useful tool to monitor the relationship between pain and 

 
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cannabis use. Text messaging is an effective method to modify health behaviors, monitor 
substance use, and track pain52. Our group has recently demonstrated the feasibility of using 
short message service (SMS) texting to promote ART adherence and monitor daily 
methamphetamine (METH) use in PLWH with bipolar disorder or METH dependence, but SMS 
has not been used to assess cannabis exposure in this population53, 54. There are a variety of 
cannabis mobile apps providing information on strain and dispensary information, but none that 
address abuse, addiction, or treatment55. Ecological momentary assessment (EMA), the 
technique of gathering data within a participant’s environment using multiple assessments56, 
has been applied to alcohol and cigarette use57, but few studies have examined cannabis. We 
will utilize a novel text messaging protocol, Individual Monitoring of Pain And Cannabis Taken 
(IMPACT), to assess the relationship between real-world self-administered cannabis and 
changes in pain symptoms that precede and follow drug exposure. 
 
 
2.0 
STUDY DESIGN  
 
Our objective is to assess 100 community-dwelling PLWH with neuropathic pain (PLWH-NP) 
who are recruited and tested at the HIV Neurobehavioral Research Program (HNRP)/Center for 
Medicinal Cannabis Research (CMCR) facilities located at the UCSD Medical Center. These 
participants will be enrolled in a study that consists of two stages: 1) administration of three 
different doses of vaporized cannabis obtained from NIDA (one dose per day on three separate 
days) that contain THC and varying concentrations of CBD, including: a) 2 vials of 0.01% CBD + 
1.9% THC, b) 1 vial of 0.01% CBD + 1.9% THC and 1 vial of 5.1% CBD + 1.4% THC, and c) 2 
vials of 5.1% CBD + 1.4% THC; 2) participation in a 6-month text message monitoring study, 
the Individual Monitoring of Pain and Cannabis Taken (IMPACT), where pain and cannabis use 
from local dispensaries is tracked. We will use a randomized crossover design where all 
participants receive each of the three cannabis doses at the HNRP and then are subsequently 
enrolled into IMPACT. We will recruit individuals who are currently using cannabis at least once 
a month to treat pain. The primary outcome measures of the study will examine: 1) the acute 
effects of NIDA-obtained cannabis on pain, EC levels, and the relationship with HRV (Aim 1); 2) 
the association between dispensary-obtained cannabis and changes in pain reported via 
IMPACT (Aim 2); 3) the effect of chronic THC and CBD exposure on longitudinal changes in 
pain, EC measures, and neurocognitive performance (Aim 3). Secondary and exploratory 
analyses will compare NIDA-obtained and dispensary-obtained cannabis effects on neuropathic 
pain and evaluate if there are different effects of reported cannabis strain (Sativa, Indica), specific 
cannabis products (e.g., OG Kush, Sour Lemon, etc.), or mode (smoking, vaporizing, ingesting 
food product) on pre-post drug exposure changes in pain 
 
3.0 
SELECTION AND ENROLLMENT OF PARTICIPANTS 
 
3.1 
Inclusion Criteria 
 
3.1.1   Ability of participant to provide informed consent. 
3.1.2   Age 18 or older. 
3.1.3   HIV-1 infection documented by any FDA licensed clinical test including HIV 
enzyme/antigen test or chemiluminescence immunoassay (E/CIA) or plasma 

 
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HIV-1 RNA viral load. 
3.1.4    A diagnosis of HIV sensory neuropathy determined by a neurological exam 
performed by a nurse and defined per previous criteria7, 59 as one or more clinical 
signs, including diminished or dull/sharp sensation in feet or reduced ankle 
reflexes. 
3.1.5   Current use of cannabis 
 
3.1.6    Ability to describe THC and CBD content in cannabis products 
 
3.1.7   Ability to respond to text messages 
 
3.2 
Exclusion Criteria 
 
           3.2.1  Meeting criteria for current alcohol or substance dependence 
           3.2.2  Traumatic brain injury 
           3.2.3  Dementia or Alzheimer’s disease 
           3.2.4   Psychosis 
3.2.5    A respiratory condition, i.e., pulmonary disease, that would be exacerbated by 
inhaling vaporized cannabis. 
            3.2.6   History of cardiovascular disease, including myocardial infarction or stroke 
3.2.7   Uncontrolled hypertension, defined as a systolic blood pressure greater than 150 
mm Hg or a diastolic blood pressure greater than 100 mm Hg. 
3.2.8   Pregnancy, breastfeeding, or unwillingness to prevent pregnancy during the 
cannabis administration portion of the study (using birth control in female 
participants of child-bearing age). 
3.2.9  Unwillingness or inability to receive or respond to text messages. 
 
 
 
4.0 
STUDY TREATMENT 
 
 
4.1 
NIDA Drug Supply Provision of Cannabis Product 
 
We will be administering three cannabis doses to each participant using the vaporizer, including 
varying concentrations of CBD (low, medium, high): a) 2 vials of 0.01% CBD + 1.9% THC, b) 1 
vial of 0.01% CBD + 1.9% THC and 1 vial of 5.1% CBD + 1.4% THC, and c) 2 vials of 5.1% 
CBD + 1.4% THC. 
 

 
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4.2 
Cannabis Administration Protocol 
 
Participants will receive vaporized cannabis using Volcano vaporizers (Storz and Bickel) with 
the aforementioned concentrations of CBD and THC at each of three visits. Allocation 
assignment of visits will be assigned using randomization schedule prepared by our statistician. 
The allocation schedule will be kept in the pharmacy and concealed from other study personnel. 
The cannabis will be stored in a freezer at 20°C until the day before use. At least 12 hours 
before each session, 800 mg of study cannabis will be thawed. The vaporization session will be 
performed in a HNRP negative pressure room designed to prevent the vapor from being 
transferred to rooms in which other occupants of the 
building are working. Puffs from the vaporizer balloon will 
be standardized so that a consistent amount is inhaled. 
This will be done according to a cued-smoking procedure 
shown to produce reliable increases in plasma THC 
levels65. A nurse will provide instructions to participants to 
‘inhale’ (5 seconds), ‘hold smoke in lungs’ (10 seconds), 
and ‘exhale’ and to wait before repeating the puff cycle (40 seconds). Each participant will 
inhale 4 puffs at each session, an amount that was well tolerated during our previous human 
laboratory experiments 60. We will measure vital signs (heart rate, respiration), pain intensity 
measured by a 0 to 10 numerical rating scale, and HRV at baseline (30 minutes before 
cannabis administration), at time zero (immediately after cannabis administration), and at 60, 
120, and 180 minutes after drug administration. As a secondary measure of pain relief, we will 
use the Patient Global Impression of Change (PGIC) that will be measured hourly following 
administration of study medications. We will also conduct a von Frey assessment. The von Frey 
tool consists of monofilaments that are applied to the skin until bending of the filament occurs, 
calibrated to a specific pressure and designed to minimize movement artifacts66. Increased pain 
to von Frey stimulation occurs in NP and clinical trials indicate that cannabis treatment can 
reduce allodynia on this test67. We will include this measure in our battery and assess pain 
using the VAS as previously reported67; the von Frey filament will be applied on the dorsum of 
the more painful foot until bending is observed for 3 seconds, followed by a VAS pain rating.  
 
To assess participant perception of drug effects, the Marijuana subscale (M-scale) of the 
Addiction Research Center Inventory (ARCI) will be administered68. The M-scale has 12 
true/false statements describing the subjective effects of marijuana (see attached ARCI 
Marijuana subscale). We have elected not to include a placebo in the current design because 
participants with prior cannabis use are likely to be aware they are not receiving the drug, given 
the lack of psychoactive/physiological effects, and this may confound their report of pain. We 
have also chosen to administer one fixed dose (8 puffs) to all participants to avoid the confound 
of varying levels of drug intake. Participants will be allowed to engage in normal activities, such 
as reading or listening to music between assessments. Participants will remain in the laboratory 
under direct observation by nursing staff for 3.5 hours after the vaporization inhalations are 
completed (30 minutes after the 180-minute sample collection). At that time a final vital sign 
status check will be made and upon satisfactory readings, the subject will be released and 
driven back to his/her domicile by taxicab or prearranged transportation.  
 
 
 
  Baseline       0            60            120           180 
                                         Minutes 
4 puffs vaporized cannabis 

 
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4.3.   IMPACT  
 
All participants will be instructed on how to use the IMPACT text messaging/website survey 
program, practice the SMS interface with study staff, and set up personalized preferences (e.g., 
optimal times to receive messages). If they do not have a cell phone capable of receiving and 
sending text and picture messages, one will be provided to them at the baseline session and we 
will purchase bulk ‘minutes’ in order to provide the text message intervention. Participants will 
also receive digital milligram scales that they can use to weigh out cannabis products, including 
joints, blunts, and bowls. Participants will not be required to use the scales, but they will be 
provided as an optional tool to improve the accuracy of reporting cannabis quantity. Participants 
will not be responsible should they lose or break the devices. We will also ask participants to 
identify the source of their cannabis products, including the name of the medical dispensary 
where the product was obtained. If the participant obtained cannabis from another source, such 
as a neighbor or friend, this source will be anonymously identified as “friend”. We will not collect 
any names or any identifying information about any specific individuals who provide cannabis to 
the participant; only the names of medical dispensaries in San Diego will be collected. 
Participants will also not be required to disclose the source of the cannabis and may select an 
option of “decline to provide” or “I do not know” or “unknown” when asked about this information. 
(45 minutes). After the 6-month IMPACT is completed, participants will return for a visit that will 
include the same assessments during the pre-entry visit, including a medical exam with 
neuropathy testing, assessment of substance use, administration of pain rating scales, 
neurocognitive testing, and a blood draw to repeat baseline evaluations including THC, CBD, 
and EC biomarkers and check hepatic/renal function. We will not administer cannabis at this 
session, and similar to the pre-entry visit, request that participants abstain from cannabis for 24 
hours before this visit.  
 
 
5.0 
CLINICAL MANAGEMENT ISSUES 
 
5.1 
Adverse Events  
 
The medical response to adverse events (AE) or serious adverse events (SAE) will be managed 
and assessed under the on-site direction of our medical team. An AE is defined as any 
unfavorable and unintended sign (including an abnormal laboratory finding), symptom, or 
disease temporally associated with the use of a medical treatment or procedure regardless of 
whether it is considered related to the medical treatment or procedure. An SAE is defined as the 
following: an AE that results in death, is life-threatening (even if temporary in nature), results in 
a permanent impairment of body function or permanent damage to body structure, 
hospitalization, prolongation of hospitalization, or medical or surgical intervention to preclude 
permanent impairment of a body function or permanent damage to a body structure, or 
represents a serious medical event.  
 
AE associated with acute cannabis exposure may include the following: 1) likely effects: 
difficulty with balance, eye irritation, throat irritation, increased heart rate, possible low blood 
pressure, reversible problems with appetite; 2) less likely effects: changes in mood (euphoria or 
dysphoria), loss of memory, decreased ability to concentrate or think properly; 3) rare but 

 
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serious effects: dizziness, head and chest pressure, disorientation, agitation, combativeness, 
incoherence, or visual hallucinations. 
If requested by the research team, a personal assessment of the participant will be performed. 
Participants will be followed by the research team until such time as the adverse event resolves. 
A Registered Nurse and/or research associate will consult with study PIs to discuss each 
adverse event. In the event of any uncertainty, the decision as to whether or not the adverse 
event is to be labeled a SAE will be made by a Medical Officer. If deemed not to be a SAE, the 
AE will be reported at the time of the UCSD IRB continuing review or annual review by the FDA 
and NIDA.  
 
All AEs will be collected on an Adverse Event log which will include the Patient ID, date, visit 
number, time in 24-hour format, description of adverse event, date of resolution if applicable, 
determination if related to the study, and date reported to UCSD IRB and study sponsor (NIDA). 
All AEs experienced by the participant, i.e., from the time of study drug administration through 
the end of the study, will be reported on this log. Any AE or SAE so recorded will be reported 
annually to the Human Research Protection Program (HRPP) at UCSD. In the event of an SAE,  
the PIs will report SAE to the UCSD IRB within 10 days as required by the HRPP. Such data will 
also be promptly reported to NIDA. Any AE and SAE reported may result in revisions to the study 
protocol. If so, these revisions will be submitted to the UCSD IRB for review. Any unexpected fatal 
or life threatening experiences associated with the use of the drug (21 CFR 312[.32[c] [ii] [2]) will 
be reported to the FDA via telephone or facsimile transmission within 7 calendar days after 
NIDA’s initial receipt of the information. In accordance with FDA Code of Federal Regulations, 
the investigators will be responsible for reporting of SAE's directly to the FDA using the 
mandatory reporting form FDA 3500A.  
 
 
5.2 
Toxicity  
 
Our group has previously administered a similar dose of THC (3.5%) to participants in prior 
studies using both cigarettes (Wilsey B, Marcotte T, Tsodikov A, et al. A randomized, placebo-
controlled, crossover trial of cannabis cigarettes in neuropathic pain. J Pain. Jun 2008;9(6):506-
521) and vaporized cannabis (Wilsey B, Marcotte T, Deutsch R, Gouaux B, Sakai S, Donaghe 
H. Low-dose vaporized cannabis significantly improves neuropathic pain. J Pain. Feb 
2013;14(2):136-148). In both studies his findings indicated that none of the participants 
receiving 3.5% THC exhibited any AE or SAE due to drug exposure.  Based on the data he has 
collected, we do not anticipate AE or SAE due to acute THC exposure in the current study 
(1.4% to 1.9%). In addition, we will be recruiting participants with a history of cannabis use 
rather than cannabis-naïve individuals; therefore, there is also lower risk of a novel AE or SAE 
occurring in these participants. 
 
CBD does not bind to the known cannabinoid receptors and its mechanism of action is yet 
unknown86. The administration of CBD appears to be much less problematic compared to THC. 
In a recent study comparing oral THC, CBD, and placebo in healthy volunteers87, CBD was well 
tolerated and there were no differences between oral CBD and placebo on symptomatic or 
physiological variables. Other work suggests that CBD may in fact attenuate some of the 
psychoactive effects of THC88-90. After an extensive literature review, Bergamaschi and 

 
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colleagues concluded that CBD is a substance with low toxicity91. Based on these findings, we 
do not anticipate that there will be AE or SAE due to acute CBD administration in the study. 
However, no specific research on vaporized combinations of THC/CBD has been performed 
and we will collect data at every visit on any adverse effects that occur. 
 
5.3 
Monitoring Participant Safety 
 
Ongoing medical treatment for HIV will not be altered or modified in any way for research 
purposes. During the initial enrollment and screening process, participants will be informed 
about potential events that may occur as a result of cannabis exposure and will be asked to 
contact the staff if any adverse events occur during study participation. Vital signs will be 
monitored during the cannabis administration procedure at hourly intervals to monitor the 
participant’s health status. At any sign of an adverse reaction (e.g. a change in blood pressure 
or heart rate or development of psychological distress), medical staff will be contacted. 
Participants will be monitored by medical staff until such time as the adverse event resolves. In 
the event of a medical emergency, participants can be transported to the UCSD Medical Center 
Emergency Room. Participants will remain in the laboratory under direct observation by nursing 
staff for 3.5 hours after the cannabis vaporization inhalations are completed. At that time a final 
vital sign and self-report status check will be made and upon satisfactory readings, the subject 
will be released and driven back to his/her domicile by taxicab or prearranged transportation. 
The return transport procedure also will be observed directly by staff to ensure compliance. In 
an emergency situation that occurs outside of the university where participants are in need of 
immediate help as a result of an adverse event, the participants will be informed that they 
should first call 911 and then report the incident to the study staff as soon as possible. During 
IMPACT participants will also receive regular text messages that will solicit information about 
any adverse events associated with their self-administered cannabis use. Participant text logs 
will be monitored on a daily basis to ensure that no serious problems have occurred and to 
supervise each individual’s continuing participation in the study. Participants are informed that 
they may withdraw from the research at any time if they find any aspect objectionable. 
 
 
6.0 
CRITERIA FOR DISCONTINUATION 
 
6.1 
Criteria for Discontinuation of Cannabis Administration 
 
All participants will be informed of the risks of the study and the anticipated and potential effects 
of exposure to vaporized cannabis. We will monitor participant status throughout the day of the 
cannabis administration sessions, including assessing blood pressure at regular intervals (60, 
120, 180 minutes after drug administration).  
 
Stopping rules for study subject discontinuation include: 
Pulse:   
       pulse rate > 130 beats per minute or < 50 beats per minute 
Blood Pressure:     systolic blood pressure > 160 mmHg or < 80 mmHg,  
 
 
       diastolic blood pressure > 100 mmHg or < 40 mmHg 
Respiratory: shortness of breath, respiratory rate > 22 breaths per minute, or 
oxygen saturation less than 92%  
Cardiac: chest pain 

 
14 
 
  
  
 
 
 
 
Neuro: confusion, loss of coordination, falling down, fainting 
Psych: panic attack, psychotic reaction (hallucinations, psychotic depression) 
 
6.2 
Premature Study Discontinuation  
 
8.2.1    Pregnancy or breast feeding. 
 
8.2.2    Request by the subject to withdraw. 
 
8.2.3    At the discretion of the investigators, UCSD IRB, NIDA, or other agencies 
providing oversight, i.e., Research Advisory Panel of California. 
 
8.2.4.   Rare but serious side effects of cannabis administration as listed in Section 6.1. 
 
 
7.0 
STATISTICAL ANALYSIS PLAN  
 
 
7.1  
Aim 1 Measures and Analyses  
 
Data will be assessed for normality and transformations applied as needed (e.g., log). 
Neuropathic pain before and after acute cannabis administration will be assessed by NPRS and 
the von Frey test. Plasma AEA and 2-AG will be measured with LC/MS. Flow cytometry will 
quantify the percentage of PBMC that express CB2, FAAH, and MAGL, including monocytes, 
CD4+ T-cells, and CD8+ T-cells. To examine the effect of different CBD/THC products on NP 
and EC biomarkers, we will use a linear mixed model with subjects treated as a random effect to 
model the response measures. This methodology takes into account the repeated measures 
aspect of the within-subjects crossover study design, incorporating information from 
observations for each subject at different treatment doses and multiple time points within each 
dose. For initial modeling, terms will include dose (0.01%, 5.1% - 4 puffs, and 5.1% - 8 puffs) 
CBD treated as a categorical variable), time (0, 60, 120 and 180 minutes after exposure treated 
as a continuous variable), and dose x time interaction. Additional terms will also be included for 
the sequence in which the treatments were administered (e.g., low CBD vs. medium CBD) and 
for second-order time (time2). The quadratic term is intended to model a U-shaped response 
curve if responses initially increase (or decrease), reach a maximum (or minimum), then 
decrease (or increase) back to baseline levels. For each outcome measure, each of these last 2 
terms will be omitted from subsequent models and not reported if nonsignificant. Any potential 
factors that associate with outcome variables at the α = 0.20 level in single-predictor analyses 
(history of light vs. heavy cannabis use, mode of prior cannabis use – i.e., engaging in smoking, 
or vaporizing, or both), time since last cannabis use before baseline, duration of cannabis use 
over lifetime, presence of adolescent cannabis use, duration of HIV infection, nadir CD4, viral 
load, gender, the presence of other non-cannabis analgesic medications, history of non-cannabis 
substance use disorders) will be included in the linear model. Dose effects at each time point will 
be assessed with mixed modeling after re-coding time as a categorical factor and including dose 
and dose x time terms (plus a term for sequence if this is significant in the initial model). 
Differences among doses will be evaluated using the Tukey honestly significant difference 
(HSD) comparison tests for differences of effects over all time points and contrasts within each 

 
15 
 
  
  
 
 
 
 
time point. All response observations, including information from subjects who do not complete 
all experimental sessions, will be included in the analyses. Similar mixed-model analyses will be 
performed on the primary pain outcome after adjustment for psychomimetic side effects 
(measured with the ARCI scale) to assess for effects of the study drug on pain independent of 
subjective responses. The proportion of subjects with a 30% pain reduction, a standard for 
effective pain reduction60 will be compared between each of the doses with chi-square tests; we 
will also calculate the number needed to treat (NNT) for a 30% pain reduction rate. We will also 
conduct analyses to examine the association between pain and EC biomarkers, including AEA, 
2-AG, FAAH, and MAGL expression. A 5% significance level will be used for all testing. The 
association of pain levels with HRV will use a linear mixed-effects model, adjusting for potential 
confounders as above. Within-subject correlation will be accounted for using subject-specific 
random intercepts and slopes. 
 
7.2  
Aim 2 Measures and Analyses  
 
Based on our existing data for PLWH SMS compliance, we anticipate that participants will 
respond to 80-90% of the daily text messages during IMPACT. To address the issue of missing 
data, we will incorporate questions that allow participants to indicate their pain and cannabis use 
for the prior day if they did not respond to the earlier message. For days that have completely 
missing data, we will treat the intermittently missing data as missing completely at random.  
However, this assumption will be checked in sensitivity analyses by comparing the outcomes of 
participants based on the amount of missing data.  Study dropout will be examined separately 
using statistical methods in current use [Diggle, Heagerty, Liang, and Zeger, Analysis of 
Longitudinal Data, 2nd ed., Oxford University Press, 2013]:  The relationship between CBD, 
THC, and the CBD/THC ratio during a cannabis exposure event to changes in pain before and 
after the event will be examined using longitudinal data methods – e.g., mixed-effects linear 
models, controlling for potential confounders including baseline pain, in addition to those listed 
under Aim 1. The total CBD and THC consumed during the exposure will be calculated using the 
SUI method, estimating total grams of cannabis consumed multiplied by the percentages of CBD 
and THC content. Subject-specific random intercepts will be included in the model in order to 
account for the within-subject correlation of the outcome. Exploratory analyses will examine if 
there are different effects of reported cannabis strain (Sativa, Indica), individual types (e.g., OG 
Kush, Sour Lemon, etc.), or mode (smoking, vaporizing, ingesting food product) on pre-post 
changes in NP. We will also conduct exploratory analyses to examine if there is an interaction 
between reported levels of THC (low, < 1%, medium, 1-6%, high, > 10%) and CBD (low, < 1%, 
medium, 1-6%, high, > 10%) on pain change after drug use. The association of daily measures of 
pain levels with HRV will use a linear mixed-effects model, adjusting for potential confounders.  
The within-subject correlation will be accounted for using subject-specific random intercepts. 
Longitudinal changes in HRV between the first and last week will be assessed with a linear 
model that includes cannabis use (light vs. heavy) and CBD/THC intake, as predictors. 
Regression analyses will also examine the association between HRV and self-report pain 
measures quantified at the baseline and final visits. 
 
Comparison of NIDA-obtained and dispensary-obtained cannabis effects on NP. We will 
compare the effect of laboratory cannabis administration and IMPACT self-report data on 
changes in pain (both measured with NPRS) before and after drug exposure. We will assess 
pain change scores for the laboratory study and IMPACT measured as the difference between 

 
16 
 
  
  
 
 
 
 
baseline (before drug) and 60 and 120 minutes after drug, time points that correspond with pain 
reduction in our prior THC work60. We will use the following analyses: 1) plot the distribution of 
the CBD/THC ratio (x- axis) against pain change (y-axis), calculate the slope of pain change 
scores for both the lab data and IMPACT, and determine if the slopes are similar or significantly 
different (a mixed effect model that will estimate changes in outcomes/slopes). 2) If the slopes 
are nonlinear, we will calculate the area under the curve (AUC) – a measure of total pain 
change – up to a CBD/THC ratio of 10 (our high CBD dose in the lab). 3) It is possible that our 
IMPACT data show that many participants only use one or two types of cannabis (e.g., with only 
a single CBD/THC ratio), thus it might be difficult to plot a CBD/THC ratio distribution. In that 
event, we will classify IMPACT cannabis use into 3 categories (low CBD/THC ratio, < 1; 
matched CBD/THC 1:1; high CBD/THC ratio, >1, and examine the correlation between the pain 
change in each category (averaged over the IMPACT study) with the pain change scores we 
observe for our low, medium, and high CBD laboratory doses. If our findings indicate a higher 
slope or greater AUC for NIDA cannabis vs. dispensary cannabis, this would suggest less 
efficacious pain relief from the local cannabis sources. In contrast, a strong correlation between 
CBD pain change scores for NIDA and dispensary product in one or more CBD/THC ratio 
categories would support a consistent finding for the effectiveness of different CBD amounts. In 
summary, either agreement or discrepancy between NIDA and dispensary data would be highly 
informative and would help guide future policy recommendations for cannabis-based pain 
treatment. 
 
7.3 
Aim 3 Measures and Analyses  
 
We will use a linear model to examine the association between the total CBD, THC, and 
CBD/THC ratio during IMPACT and the change in NP, disease markers (CD4, viral load, Total 
Neuropathy Score, and neurocognitive global T-score), and EC biomarkers (AEA, 2-AG, FAAH, 
MAGL, CB2) from baseline to the final visit after month 6. We will control for confounders as in 
Aims 1 and 2, including any CBD and THC levels recorded at the baseline and final sessions. 
Linear models will compare the month 6 – baseline change in pain and in EC biomarkers 
between the heavy- and light-cannabis groups. One exploratory analysis will test for an 
interaction between group (light vs. heavy) and CBD and THC levels on change in NP and EC 
biomarkers. We will assess if exposure mode (smoking/vaporizing/ingestion) predicts pain 
outcome. We will examine if there is an association between pain change over time and 
changes in EC biomarkers. During the 6-month IMPACT, alterations may occur in cannabis use 
or pain medication (e.g., a person enrolled as a light cannabis user may start to engage in 
heavy use or begin using non-cannabis medication for pain, i.e., an opiate, which we will record 
with IMPACT). To address these issues we will conduct light vs. heavy use analyses based both 
on the baseline group classification and the actual use during IMPACT, include a cannabis use 
‘change’ factor in the analyses (going from light to heavy use, or vice versa), and include the 
initiation of any non-cannabis pain medication as a factor in the model. 
 
 
7.4  
Power Analyses  
 
A recent study indicated a medium effect size (Cohen’s d = 0.46) for CBD treatment that 
increased plasma AEA levels compared to an antipsychotic drug control condition26. Preclinical 
models of neuropathic pain in mice demonstrate that FAAH inhibitors decrease hyperalgesia 

 
17 
 
  
  
 
 
 
 
and allodynia with large effect sizes (Cohen’s d = 4-5)18. Our pilot HRV data indicate a medium 
to large effect size (Cohen’s d = 0.8) for reduced RMSSD in PLWH with neuropathic pain 
compared to PLWH without neuropathy. We conducted power calculations with the G*POWER 
software92 comparing the area under the curve (AUC) of the change from baseline in pain levels 
between the three doses of cannabis.  The actual analyses will have higher power, since they 
rely on a longitudinal mixed-effects model. With n=100 participants completing the cross-
sectional baseline visits, and measured in a within-participant design, as described above, we 
have 80% power to detect an effect size Cohen’s f=0.180.  This Cohen’s f corresponds to a 
range of group means for the three groups corresponding to a small-to-medium Cohen’s d = 
0.382-0.441.  We have 0.61-0.76 power to detect such a pairwise difference as statistically 
significant in post-hoc analyses (e.g., with Bonferroni correction for post-hoc comparisons).  If 
the completion rate at this stage is 95% (90%) of the initial enrollment of n=100, the detectable 
effect size is Cohen’s f=0.185 (0.190).  These correspond to a range of group means for the 
three groups corresponding to small-medium Cohen’s d = 0.403-0.465. 
 
For Aim 2, with 20% attrition over the 6 months of IMPACT we have n= 80 participants with 6 
months (26 weeks) of data.  We conservatively ignore the drop-out participants (who 
nonetheless contribute partial data).  Assume, conservatively, that participants will use cannabis 
on average 2 times/week.  This gives n=80 and k=52 observations/participant.  If ICC is the 
intra-class, or within-participant correlation, the effective sample size (number of equivalent 
independent observations) is neff = n/(ICC+(1-ICC)/k) ≈ n/ICC [e.g., Killip, Mahfoud, Pearce.  
What is an intracluster correlation coefficient?  Crucial concepts for primary care researchers, 
Ann Fam Med, 2004; 2:204-208.].  Assuming conservatively =0.5 (or lower), we get neff = 2n = 
200 [neff = 160].  We have 80% power to detect a (partial) correlation R between the individual 
predictors (Hypothesis 1: CBD, THC, and the CBD/THC ratio; Hypothesis 2: pain levels and 
HRV) and change in pain of R = 0.218 (or semi-partial R2 = 0.0475), after adjusting for 
confounders.  Calculations used G*Power.  
 
For Aim 3, assuming n = 80 participants complete the 6-month follow-up, we have 80% power 
to detect an association between an individual predictor and response (e.g., total CBD and 
changes in neuropathic pain levels) of R = 0.302 (or semi-partial R2 = 0.092), after adjusting for 
confounders.  The calculations used G*Power. 
 
 
 
8.0 
PARTICIPANTS 
 
 
8.1 
Monitoring 
 
The study team will review all adverse events during the study by cumulative reports on a 
monthly basis. A Data Monitoring Committee (DMC) will review the study for safety yearly.  The 
study will only be stopped early if there are serious safety concerns.  
 
The following items will be included in the yearly DMC meetings: 
• 
Progress of the study, including participant recruitment, accrual and retention.  
• 
Number of premature discontinuations and reasons for discontinuation 

 
18 
 
  
  
 
 
 
 
• 
Compliance with study treatment and adherence to IMPACT 
• 
Safety and treatment toxicity, including summary of any AE and SAE 
• 
Any protocol violations 
 
 
8.2 
Institutional Review Board (IRB) Review and Informed Consent 
 
This protocol and the informed consent document and any subsequent modifications will 
be reviewed and approved by the IRB responsible for oversight of the study. A signed 
consent form will be obtained from the participant (or parent, legal guardian, or person 
with power of attorney for participants who cannot consent for themselves). The consent 
form will describe the purpose of the study, the procedures to be followed, and the risks 
and benefits of participation. A copy of the consent form will be given to the participant, 
parent, or legal guardian, and this fact will be documented in the participant’s record. 
 
8.3 
Participant Confidentiality 
 
All laboratory specimens, evaluation forms, reports, and other records that leave the site 
will be identified by coded number only to maintain participant confidentiality. All records 
will be kept locked. All computer entry and networking programs will be done with coded 
numbers only. Clinical information will not be released without written permission of the 
participant, except as necessary for monitoring by the, IRB and/or DMC.   
 
8.4 
Study Discontinuation 
 
The study may be discontinued at any time by the IRB and/or DMC as part of their duties 
to ensure that research participants are protected. 
 

 
19 
 
 
9.0 
REFERENCES 
 
1. 
Mann R, Sadosky A, Schaefer C, Baik R, Parsons B, Nieshoff E, Stacey BR, Tuchman 
M, Nalamachu S. Burden of HIV-Related Neuropathic Pain in the United States. J Int 
Assoc Provid AIDS Care. 2015. 
2. 
Malvar J, Vaida F, Sanders CF, Atkinson JH, Bohannon W, Keltner J, Robinson-Papp J, 
Simpson DM, Marra CM, Clifford DB, Gelman B, Fan J, Grant I, Ellis RJ. Predictors of 
new-onset distal neuropathic pain in HIV-infected individuals in the era of combination 
antiretroviral therapy. Pain. 2015;156(4):731-739. 
3. 
Robinson-Papp J, Morgello S, Vaida F, Fitzsimons C, Simpson DM, Elliott KJ, Al-Lozi 
M, Gelman BB, Clifford D, Marra CM, McCutchan JA, Atkinson JH, Dworkin RH, 
Grant I, Ellis R. Association of self-reported painful symptoms with clinical and 
neurophysiologic signs in HIV-associated sensory neuropathy. Pain. 2010;151(3):732-
736. 
4. 
Ellis RJ, Rosario D, Clifford DB, McArthur JC, Simpson D, Alexander T, Gelman BB, 
Vaida F, Collier A, Marra CM, Ances B, Atkinson JH, Dworkin RH, Morgello S, Grant I. 
Continued high prevalence and adverse clinical impact of human immunodeficiency 
virus-associated sensory neuropathy in the era of combination antiretroviral therapy: the 
CHARTER Study. Arch Neurol. 2010;67(5):552-558. 
5. 
Phillips TJ, Cherry CL, Cox S, Marshall SJ, Rice AS. Pharmacological treatment of 
painful HIV-associated sensory neuropathy: a systematic review and meta-analysis of 
randomised controlled trials. PLoS One. 2010;5(12):e14433. 
6. 
Abrams DI, Jay CA, Shade SB, Vizoso H, Reda H, Press S, Kelly ME, Rowbotham MC, 
Petersen KL. Cannabis in painful HIV-associated sensory neuropathy: a randomized 
placebo-controlled trial. Neurology. 2007;68(7):515-521. 
7. 
Ellis RJ, Toperoff W, Vaida F, van den Brande G, Gonzales J, Gouaux B, Bentley H, 
Atkinson JH. Smoked medicinal cannabis for neuropathic pain in HIV: a randomized, 
crossover clinical trial. Neuropsychopharmacology. 2009;34(3):672-680. 
8. 
Wilsey B, Marcotte T, Tsodikov A, Millman J, Bentley H, Gouaux B, Fishman S. A 
randomized, placebo-controlled, crossover trial of cannabis cigarettes in neuropathic 
pain. J Pain. 2008;9(6):506-521. 
9. 
Wallace M, Schulteis G, Atkinson JH, Wolfson T, Lazzaretto D, Bentley H, Gouaux B, 
Abramson I. Dose-dependent effects of smoked cannabis on capsaicin-induced pain and 
hyperalgesia in healthy volunteers. Anesthesiology. 2007;107(5):785-796. 
10. 
Johnson JR, Burnell-Nugent M, Lossignol D, Ganae-Motan ED, Potts R, Fallon MT. 
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. 2010;39(2):167-179. 
11. 
Varvel SA, Wiley JL, Yang R, Bridgen DT, Long K, Lichtman AH, Martin BR. 
Interactions between THC and cannabidiol in mouse models of cannabinoid activity. 
Psychopharmacology (Berl). 2006;186(2):226-234. 
12. 
Hermann D, Schneider M. Potential protective effects of cannabidiol on neuroanatomical 
alterations in cannabis users and psychosis: a critical review. Curr Pharm Des. 
2012;18(32):4897-4905. 
13. 
Woodhams SG, Sagar DR, Burston JJ, Chapman V. The role of the endocannabinoid 
system in pain. Handb Exp Pharmacol. 2015;227:119-143. 

 
20 
 
 
14. 
Haj-Dahmane S, Shen RY. Modulation of the serotonin system by endocannabinoid 
signaling. Neuropharmacology. 2011. 
15. 
Pertwee RG. Ligands that target cannabinoid receptors in the brain: from THC to 
anandamide and beyond. Addict Biol. 2008;13(2):147-159. 
16. 
Bari M, Rapino C, Mozetic P, Maccarrone M. The endocannabinoid system in gp120-
mediated insults and HIV-associated dementia. Exp Neurol. 2010;224(1):74-84. 
17. 
Mulvihill MM, Nomura DK. Therapeutic potential of monoacylglycerol lipase inhibitors. 
Life Sci. 2013;92(8-9):492-497. 
18. 
Roques BP, Fournie-Zaluski MC, Wurm M. Inhibiting the breakdown of endogenous 
opioids and cannabinoids to alleviate pain. Nat Rev Drug Discov. 2012;11(4):292-310. 
19. 
Racz I, Nadal X, Alferink J, Banos JE, Rehnelt J, Martin M, Pintado B, Gutierrez-Adan 
A, Sanguino E, Manzanares J, Zimmer A, Maldonado R. Crucial role of CB(2) 
cannabinoid receptor in the regulation of central immune responses during neuropathic 
pain. J Neurosci. 2008;28(46):12125-12135. 
20. 
Leweke FM, Giuffrida A, Koethe D, Schreiber D, Nolden BM, Kranaster L, Neatby MA, 
Schneider M, Gerth CW, Hellmich M, Klosterkotter J, Piomelli D. Anandamide levels in 
cerebrospinal fluid of first-episode schizophrenic patients: impact of cannabis use. 
Schizophr Res. 2007;94(1-3):29-36. 
21. 
Morgan CJ, Page E, Schaefer C, Chatten K, Manocha A, Gulati S, Curran HV, Brandner 
B, Leweke FM. Cerebrospinal fluid anandamide levels, cannabis use and psychotic-like 
symptoms. Br J Psychiatry. 2013;202(5):381-382. 
22. 
Bioque M, Garcia-Bueno B, Macdowell KS, Meseguer A, Saiz PA, Parellada M, 
Gonzalez-Pinto A, Rodriguez-Jimenez R, Lobo A, Leza JC, Bernardo M. Peripheral 
endocannabinoid system dysregulation in first-episode psychosis. 
Neuropsychopharmacology. 2013;38(13):2568-2577. 
23. 
Hirvonen J, Goodwin RS, Li CT, Terry GE, Zoghbi SS, Morse C, Pike VW, Volkow ND, 
Huestis MA, Innis RB. Reversible and regionally selective downregulation of brain 
cannabinoid CB1 receptors in chronic daily cannabis smokers. Mol Psychiatry. 
2012;17(6):642-649. 
24. 
Sim-Selley LJ, Schechter NS, Rorrer WK, Dalton GD, Hernandez J, Martin BR, Selley 
DE. Prolonged recovery rate of CB1 receptor adaptation after cessation of long-term 
cannabinoid administration. Mol Pharmacol. 2006;70(3):986-996. 
25. 
Villares J. Chronic use of marijuana decreases cannabinoid receptor binding and mRNA 
expression in the human brain. Neuroscience. 2007;145(1):323-334. 
26. 
Leweke FM, Piomelli D, Pahlisch F, Muhl D, Gerth CW, Hoyer C, Klosterkotter J, 
Hellmich M, Koethe D. Cannabidiol enhances anandamide signaling and alleviates 
psychotic symptoms of schizophrenia. Transl Psychiatry. 2012;2:e94. 
27. 
Guindon J, Hohmann AG. The endocannabinoid system and pain. CNS Neurol Disord 
Drug Targets. 2009;8(6):403-421. 
28. 
Fernandez-Ruiz J, Sagredo O, Pazos MR, Garcia C, Pertwee R, Mechoulam R, Martinez-
Orgado J. Cannabidiol for neurodegenerative disorders: important new clinical 
applications for this phytocannabinoid? Br J Clin Pharmacol. 2012;75(2):323-333. 
29. 
Zhornitsky S, Potvin S. Cannabidiol in humans-the quest for therapeutic targets. 
Pharmaceuticals (Basel). 2012;5(5):529-552. 
30. 
Robinson ME, O'Shea AM, Craggs JG, Price DD, Letzen JE, Staud R. Comparison of 
machine classification algorithms for fibromyalgia: neuroimages versus self-report. J 

 
21 
 
 
Pain. 2015;16(5):472-477. 
31. 
Koenig J, Jarczok MN, Ellis RJ, Warth M, Hillecke TK, Thayer JF. Lowered 
parasympathetic activity in apparently healthy subjects with self-reported symptoms of 
pain: preliminary results from a pilot study. Pain Pract. 2015;15(4):314-318. 
32. 
Koenig J, Jarczok MN, Fischer JE, Thayer JF. The Association of (Effective and 
Ineffective) Analgesic Intake, Pain Interference and Heart Rate Variability in a Cross-
Sectional Occupational Sample. Pain Med. 2015. 
33. 
Koenig J, Loerbroks A, Jarczok MN, Fischer JE, Thayer JF. Chronic Pain and Heart Rate 
Variability in a Cross-Sectional Occupational Sample: Evidence for Impaired Vagal 
Control. Clin J Pain. 2015. 
34. 
Koenig J, Rinnewitz L, Warth M, Kaess M. Autonomic nervous system and 
hypothalamic-pituitary-adrenal axis response to experimentally induced cold pain in 
adolescent non-suicidal self-injury--study protocol. BMC Psychiatry. 2015;15:150. 
35. 
Askgaard G, Kristoffersen US, Mehlsen J, Kronborg G, Kjaer A, Lebech AM. Decreased 
Heart Rate Variability in HIV Positive Patients Receiving Antiretroviral Therapy: 
Importance of Blood Glucose and Cholesterol. PLoS One. 2011;6(5):e20196. 
36. 
Chow DC, Wood R, Choi J, Grandinetti A, Gerschenson M, Sriratanaviriyakul N, 
Nakamoto B, Shikuma C, Low P. Cardiovagal Autonomic Function in HIV-Infected 
Patients with Unsuppressed HIV Viremia. HIV Clin Trials. 2011;12(3):141-150. 
37. 
Mittal CM, Wig N, Mishra S, Deepak KK. Heart rate variability in human 
immunodeficiency virus-positive individuals. Int J Cardiol. 2004;94(1):1-6. 
38. 
Zamuner AR, Barbic F, Dipaola F, Bulgheroni M, Diana A, Atzeni F, Marchi A, Sarzi-
Puttini P, Porta A, Furlan R. Relationship between sympathetic activity and pain intensity 
in fibromyalgia. Clin Exp Rheumatol. 2015;33(1 Suppl 88):S53-57. 
39. 
Weeks DL, Whitney AA, Tindall AG, Carter GT. Pilot Randomized Trial Comparing 
Intersession Scheduling of Biofeedback Results to Individuals with Chronic Pain: 
Influence on Psychologic Function and Pain Intensity. Am J Phys Med Rehabil. 
2015;94(10 Suppl 1):869-878. 
40. 
Bonn-Miller MO, Oser ML, Bucossi MM, Trafton JA. Cannabis use and HIV 
antiretroviral therapy adherence and HIV-related symptoms. J Behav Med. 2012. 
41. 
Clapper JR, Mangieri RA, Piomelli D. The endocannabinoid system as a target for the 
treatment of cannabis dependence. Neuropharmacology. 2009;56 Suppl 1:235-243. 
42. 
Crean RD, Crane NA, Mason BJ. An evidence based review of acute and long-term 
effects of cannabis use on executive cognitive functions. J Addict Med. 2011;5(1):1-8. 
43. 
Bolla KI, Eldreth DA, Matochik JA, Cadet JL. Neural substrates of faulty decision-
making in abstinent marijuana users. Neuroimage. 2005;26(2):480-492. 
44. 
Nestor L, Roberts G, Garavan H, Hester R. Deficits in learning and memory: 
parahippocampal hyperactivity and frontocortical hypoactivity in cannabis users. 
Neuroimage. 2008;40(3):1328-1339. 
45. 
Pope HG, Jr., Yurgelun-Todd D. The residual cognitive effects of heavy marijuana use in 
college students. Jama. 1996;275(7):521-527. 
46. 
Cousijn J, Wiers RW, Ridderinkhof KR, van den Brink W, Veltman DJ, Goudriaan AE. 
Grey matter alterations associated with cannabis use: results of a VBM study in heavy 
cannabis users and healthy controls. Neuroimage. 2011;59(4):3845-3851. 
47. 
Campos AC, Brant F, Miranda AS, Machado FS, Teixeira AL. Cannabidiol increases 
survival and promotes rescue of cognitive function in a murine model of cerebral malaria. 

 
22 
 
 
Neuroscience. 2015;289:166-180. 
48. 
Cheng D, Low JK, Logge W, Garner B, Karl T. Chronic cannabidiol treatment improves 
social and object recognition in double transgenic APPswe/PS1E9 mice. 
Psychopharmacology (Berl). 2014;231(15):3009-3017. 
49. 
Wright MJ, Jr., Vandewater SA, Taffe MA. Cannabidiol attenuates deficits of 
visuospatial associative memory induced by Delta(9) tetrahydrocannabinol. Br J 
Pharmacol. 2013;170(7):1365-1373. 
50. 
Molina PE, Winsauer P, Zhang P, Walker E, Birke L, Amedee A, Stouwe CV, Troxclair 
D, McGoey R, Varner K, Byerley L, LaMotte L. Cannabinoid administration attenuates 
the progression of simian immunodeficiency virus. AIDS Res Hum Retroviruses. 
2011;27(6):585-592. 
51. 
Milloy MJ, Marshall B, Kerr T, Richardson L, Hogg R, Guillemi S, Montaner JS, Wood 
E. High-intensity cannabis use associated with lower plasma human immunodeficiency 
virus-1 RNA viral load among recently infected people who use injection drugs. Drug 
Alcohol Rev. 2015;34(2):135-140. 
52. 
de la Vega R, Miro J. mHealth: a strategic field without a solid scientific soul. a 
systematic review of pain-related apps. PLoS One. 2014;9(7):e101312. 
53. 
Moore DJ, Montoya JL, Blackstone K, Rooney A, Gouaux B, Georges S, Depp CA, 
Atkinson JH, Tmarc Group T. Preliminary Evidence for Feasibility, Use, and 
Acceptability of Individualized Texting for Adherence Building for Antiretroviral 
Adherence and Substance Use Assessment among HIV-Infected Methamphetamine 
Users. AIDS Res Treat. 2013;2013:585143. 
54. 
Moore DJ, Poquette A, Casaletto KB, Gouaux B, Montoya JL, Posada C, Rooney AS, 
Badiee J, Deutsch R, Letendre SL, Depp CA, Grant I, Atkinson JH. Individualized 
texting for adherence building (iTAB): improving antiretroviral dose timing among HIV-
infected persons with co-occurring bipolar disorder. AIDS Behav. 2015;19(3):459-471. 
55. 
Ramo DE, Popova L, Grana R, Zhao S, Chavez K. Cannabis Mobile Apps: A Content 
Analysis. JMIR Mhealth Uhealth. 2015;3(3):e81. 
56. 
Serre F, Fatseas M, Swendsen J, Auriacombe M. Ecological momentary assessment in 
the investigation of craving and substance use in daily life: a systematic review. Drug 
Alcohol Depend. 2015;148:1-20. 
57. 
Shiffman S. How many cigarettes did you smoke? Assessing cigarette consumption by 
global report, Time-Line Follow-Back, and ecological momentary assessment. Health 
Psychol. 2009;28(5):519-526. 
58. 
Cherner M, Suarez P, Casey C, Deiss R, Letendre S, Marcotte T, Vaida F, Atkinson JH, 
Grant I, Heaton RK. Methamphetamine use parameters do not predict neuropsychological 
impairment in currently abstinent dependent adults. Drug Alcohol Depend. 2010;106(2-
3):154-163. 
59. 
Ellis RJ, Rosario D, Clifford DB, McArthur JC, Simpson D, Alexander T, Gelman BB, 
Vaida F, Collier A, Marra CM, Ances B, Atkinson JH, Dworkin RH, Morgello S, Grant I, 
Group CS. Continued high prevalence and adverse clinical impact of human 
immunodeficiency virus-associated sensory neuropathy in the era of combination 
antiretroviral therapy: the CHARTER Study. Arch Neurol. 2010;67(5):552-558. 
60. 
Wilsey B, Marcotte T, Deutsch R, Gouaux B, Sakai S, Donaghe H. Low-dose vaporized 
cannabis significantly improves neuropathic pain. J Pain. 2013;14(2):136-148. 
61. 
Montoya JL, Georges S, Poquette A, Depp CA, Atkinson JH, Moore DJ. Refining a 

 
23 
 
 
personalized mHealth intervention to promote medication adherence among HIV+ 
methamphetamine users. AIDS Care. 2014;26(12):1477-1481. 
62. 
Montoya JL, Wing D, Knight A, Moore DJ, Henry BL. Development of an mHealth 
Intervention (iSTEP) to Promote Physical Activity among People Living with HIV. J Int 
Assoc Provid AIDS Care. 2015. 
63. 
Montoya JL, Wing D, Knight A, Moore DJ, Henry BL. Development of an mHealth 
Intervention (iSTEP) to Promote Physical Activity among People Living with HIV. J Int 
Assoc Provid AIDS Care. 2015;14(6):471-475. 
64. 
Nunberg H, Kilmer B, Pacula RL, Burgdorf J. An Analysis of Applicants Presenting to a 
Medical Marijuana Specialty Practice in California. J Drug Policy Anal. 2011;4(1). 
65. 
Foltin RW, Brady JV, Fischman MW, Emurian CS, Dominitz J. Effects of smoked 
marijuana on social interaction in small groups. Drug Alcohol Depend. 1987;20(1):87-93. 
66. 
Fruhstorfer H, Gross W, Selbmann O. von Frey hairs: new materials for a new design. 
Eur J Pain. 2001;5(3):341-342. 
67. 
Wallace MS, Marcotte TD, Umlauf A, Gouaux B, Atkinson JH. Efficacy of Inhaled 
Cannabis on Painful Diabetic Neuropathy. J Pain. 2015;16(7):616-627. 
68. 
Martin WR, Sloan JW, Sapira JD, Jasinski DR. Physiologic, subjective, and behavioral 
effects of amphetamine, methamphetamine, ephedrine, phenmetrazine, and 
methylphenidate in man. Clin Pharmacol Ther. 1971;12(2):245-258. 
69. 
Pope HG, Jr., Gruber AJ, Hudson JI, Huestis MA, Yurgelun-Todd D. 
Neuropsychological performance in long-term cannabis users. Arch Gen Psychiatry. 
2001;58(10):909-915. 
70. 
Bouhassira D, Attal N, Alchaar H, Boureau F, Brochet B, Bruxelle J, Cunin G, 
Fermanian J, Ginies P, Grun-Overdyking A, Jafari-Schluep H, Lanteri-Minet M, Laurent 
B, Mick G, Serrie A, Valade D, Vicaut E. Comparison of pain syndromes associated with 
nervous or somatic lesions and development of a new neuropathic pain diagnostic 
questionnaire (DN4). Pain. 2005;114(1-2):29-36. 
71. 
Mathieson S, Maher CG, Terwee CB, Folly de Campos T, Lin CW. Neuropathic pain 
screening questionnaires have limited measurement properties. A systematic review. J 
Clin Epidemiol. 2015;68(8):957-966. 
72. 
Blackstone K, Iudicello JE, Morgan EE, Weber E, Moore DJ, Franklin DR, Ellis RJ, 
Grant I, Woods SP, Translational Methamphetamine ARCG. Human immunodeficiency 
virus infection heightens concurrent risk of functional dependence in persons with long-
term methamphetamine use. J Addict Med. 2013;7(4):255-263. 
73. 
Gonzalez R, Rippeth JD, Carey CL, Heaton RK, Moore DJ, Schweinsburg BC, Cherner 
M, Grant I. Neurocognitive performance of methamphetamine users discordant for 
history of marijuana exposure. Drug Alcohol Depend. 2004;76(2):181-190. 
74. 
Pederson W. Does cannabis use lead to depression and suicidal behaviours? A 
population-based longitudinal study. Acta Psychiatrica Scandinavica. 2008;118:395-403. 
75. 
Gracely RH, Kwilosz DM. The Descriptor Differential Scale: applying psychophysical 
principles to clinical pain assessment. Pain. 1988;35(3):279-288. 
76. 
Gracely RH, McGrath F, Dubner R. Ratio scales of sensory and affective verbal pain 
descriptors. Pain. 1978;5(1):5-18. 
77. 
Chapman CR, Casey KL, Dubner R, Foley KM, Gracely RH, Reading AE. Pain 
measurement: an overview. Pain. 1985;22(1):1-31. 
78. 
Melzack R. The McGill Pain Questionnaire: major properties and scoring methods. Pain. 

 
24 
 
 
1975;1(3):277-299. 
79. 
Hawker GA, Mian S, Kendzerska T, French M. Measures of adult pain: Visual Analog 
Scale for Pain (VAS Pain), Numeric Rating Scale for Pain (NRS Pain), McGill Pain 
Questionnaire (MPQ), Short-Form McGill Pain Questionnaire (SF-MPQ), Chronic Pain 
Grade Scale (CPGS), Short Form-36 Bodily Pain Scale (SF-36 BPS), and Measure of 
Intermittent and Constant Osteoarthritis Pain (ICOAP). Arthritis Care Res (Hoboken). 
2011;63 Suppl 11:S240-252. 
80. 
Heaton RK, Franklin DR, Ellis RJ, McCutchan JA, Letendre SL, Leblanc S, Corkran SH, 
Duarte NA, Clifford DB, Woods SP, Collier AC, Marra CM, Morgello S, Mindt MR, 
Taylor MJ, Marcotte TD, Atkinson JH, Wolfson T, Gelman BB, McArthur JC, Simpson 
DM, Abramson I, Gamst A, Fennema-Notestine C, Jernigan TL, Wong J, Grant I. HIV-
associated neurocognitive disorders before and during the era of combination 
antiretroviral therapy: differences in rates, nature, and predictors. J Neurovirol. 
2011;17(1):3-16. 
81. 
Press CA, Knupp KG, Chapman KE. Parental reporting of response to oral cannabis 
extracts for treatment of refractory epilepsy. Epilepsy Behav. 2015;45:49-52. 
82. 
Force HT. Heart rate variability. Standards of measurement, physiological interpretation, 
and clinical use. Task Force of the European Society of Cardiology and the North 
American Society of Pacing and Electrophysiology. Eur Heart J. 1996;17(3):354-381. 
83. 
Henry BL, Minassian A, Perry W. Effect of methamphetamine dependence on heart rate 
variability. Addict Biol. 2012;17(3):648-658. 
84. 
Henry BL, Minassian A, Paulus MP, Geyer MA, Perry W. Heart rate variability in 
bipolar mania and schizophrenia. J Psychiatr Res. 2010;44(3):168-176. 
85. 
Baumert M, Baier V, Haueisen J, Wessel N, Meyerfeldt U, Schirdewan A, Voss A. 
Forecasting of life threatening arrhythmias using the compression entropy of heart rate. 
Methods Inf Med. 2004;43(2):202-206. 
86. 
Mechoulam R, Hanus L. Cannabidiol: an overview of some chemical and 
pharmacological aspects. Part I: chemical aspects. Chem Phys Lipids. 2002;121(1-2):35-
43. 
87. 
Martin-Santos R, Crippa JA, Batalla A, Bhattacharyya S, Atakan Z, Borgwardt S, Allen 
P, Seal M, Langohr K, Farre M, Zuardi AW, McGuire PK. Acute effects of a single, oral 
dose of d9-tetrahydrocannabinol (THC) and cannabidiol (CBD) administration in healthy 
volunteers. Curr Pharm Des. 2012;18(32):4966-4979. 
88. 
Karniol IG, Shirakawa I, Kasinski N, Pfeferman A, Carlini EA. Cannabidiol interferes 
with the effects of delta 9 - tetrahydrocannabinol in man. Eur J Pharmacol. 
1974;28(1):172-177. 
89. 
Russo E, Guy GW. A tale of two cannabinoids: the therapeutic rationale for combining 
tetrahydrocannabinol and cannabidiol. Med Hypotheses. 2006;66(2):234-246. 
90. 
Zuardi AW, Shirakawa I, Finkelfarb E, Karniol IG. Action of cannabidiol on the anxiety 
and other effects produced by delta 9-THC in normal subjects. Psychopharmacology 
(Berl). 1982;76(3):245-250. 
91. 
Bergamaschi MM, Queiroz RH, Zuardi AW, Crippa JA. Safety and side effects of 
cannabidiol, a Cannabis sativa constituent. Curr Drug Saf. 2011;6(4):237-249. 
92. 
Erdfelder E, Faul F, Buchner A. GPOWER: A general power analysis program. Behavior 
Research Methods, Instruments, & Computers. 1996;28:1-11.