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A Cross-Sectional and Prospective Comparison
of Medicinal Cannabis Users and Controls
on Self-Reported Health
Nicolas J. Schlienz,
1
Ryan Scalsky,
2
Erin L. Martin,
3
Heather Jackson,
4
Joel Munson,
4
Justin C. Strickland,
5
Marcel O. Bonn-Miller,
6
Mallory Loflin,
7,8
and Ryan Vandrey
5,
*
Abstract
Introduction: Despite widespread legalization, the impact of medicinal cannabis use on patient-level health and
quality of life (QOL) has not been carefully evaluated. The objective of this study was to characterize self-reported
demographics, health characteristics, QOL, and health care utilization of Cannabis Users compared with Controls.
Methods: A longitudinal, cross-sectional web-based survey study was completed between April 2016 and
February 2018. Study participants (n=1276) were a convenience sample of either patients with a diagnosed
health condition or caregivers of a patient with a diagnosed health condition registered with the Realm of Caring
Foundation (a nonprofit organization dedicated to therapeutic cannabis research and education). Participants
were invited through e-mail to complete follow-up assessments every 3 months with 33% of participants com-
pleting one or more prospective follow-ups. Assessments included self-reported demographics, health care uti-
lization, medication use, pain, anxiety, depression, sleep, and QOL. Cannabis Users (n=808) were compared with
Controls (n=468) using negative binomial regression and linear mixed effects models testing the effect of ini-
tiation, cessation, and maintenance of medicinal cannabis use.
Results: Cannabis Users self-reported significantly better QOL [t(1054) =4.19, p<0.001], greater health satisfac-
tion [t(1045) =4.14, p<0.001], improved sleep [children: t(224) =2.90, p<0.01; adults: [t(758) =3.03, p<0.01],
lower average pain severity [t(1150) =2.34, p<0.05], lower anxiety [t(1151) =4.38, p<0.001], and lower depression
[t(1210) =5.77, p<0.001] compared with Controls. Cannabis Users reported using fewer prescription medica-
tions (rate ratio [RR] =0.86; 95% confidence interval [CI]: 0.77–0.96) and were less likely to have a past-
month emergency department visit (RR =0.61; 95% CI: 0.44–0.84) or hospital admission (RR =0.54; 95% CI:
0.34–0.87). Controls who initiated cannabis use after baseline showed significant health improvements at
follow-up, and the magnitude of improvement mirrored the between-group differences observed at baseline.
Conclusions: Cannabis use was associated with improved health and QOL. Longitudinal testing suggests that
group differences may be due to the medicinal use of cannabis. Although bias related to preexisting beliefs
regarding the health benefits of cannabis in this sample should be considered, these findings indicate that clin-
ical trials evaluating the efficacy of defined cannabinoid products for specific health conditions are warranted.
Keywords: cannabinoid therapy; cannabis; health; medicinal cannabis; quality of life
1
Department of Community Health and Health Behavior, University at Buffalo, Buffalo, New York, USA.
2
University of Maryland School of Medicine, Baltimore, Maryland, USA.
3
Department of Neuroscience, Medical University of South Carolina, Charleston, South Carolina, USA.
4
Realm of Caring Foundation, Colorado Springs, Colorado, USA.
5
Department of Psychiatry and Behavioral Sciences, Johns Hopkins University School of Medicine, Baltimore, Maryland, USA.
6
Department of Psychiatry, University of Pennsylvania Perelman School of Medicine, Philadelphia, Pennsylvania, USA.
7
Center of Excellence for Stress and Mental Health, VA San Diego Health care System, La Jolla, California, USA.
8
Department of Psychiatry, University of California San Diego, School of Medicine, La Jolla, California, USA.
*Address correspondence to: Ryan Vandrey, PhD, Behavioral Pharmacology Research Unit, Johns Hopkins University School of Medicine, 5510 Nathan Shock Dr., Baltimore,
MD 21224, USA, E-mail: rvandrey@jhmi.edu
ªNicolas J. Schlienz et al. 2020; Published by Mary Ann Liebert, Inc. This Open Access article is distributed under the terms of the Creative Commons
License [CC-BY] (http://creativecommons.org/licenses/by/4.0), which permits unrestricted use, distribution, and reproduction in any medium, provided
the original work is properly cited.
Cannabis and Cannabinoid Research
Volume 6, Number 6, 2021
Mary Ann Liebert, Inc.
DOI: 10.1089/can.2019.0096
548
Introduction
The legalization of cannabis for medicinal use without
clinical trials to demonstrate safety and efficacy is un-
precedented, yet widespread, and presents significant
regulatory challenges.
1
In the United States, more
than 2.1 million individuals are registered with state
medicinal cannabis use programs and use cannabis
for over 40 different health conditions.
2,3
The canna-
bis plant consists of hundreds of distinct chemicals,
120 of which are unique to the cannabis plant (i.e.,
phytocannabinoids).
4,5
The two most prevalent phytocannabinoids are D
9
-
tetrahydrocannabinol (THC) and cannabidiol (CBD).
THC produces many of the hallmark effects associated
with cannabis intoxication (e.g., euphoria, increased ap-
petite, dry mouth, paranoia, cognitive impairment), and
is believed to drive the abuse liability of cannabis.
6
CBD,
in contrast, does not produce THC-like intoxicating ef-
fects, has low/no abuse liability, and has been associated
with relatively few acute adverse effects in human clin-
ical trials, although additional safety data in longer du-
ration trials and populations without a large number of
concomitant medications are desired.
7,8
Although specific pharmaceutical formulations of both
THC(foranorexiaassociatedwithweightlossinpatients
with AIDS, ornauseaand vomiting associated with can-
cer chemotherapy) and CBD (Dravet syndrome or
Lennox/Gastaut syndrome)havebeenapprovedby
the Food and Drug Administration (FDA), demand
for alternative cannabis products has proliferated.
Cannabis legalization has yielded a retail market of
products that vary by formulation (e.g., dried flowers,
cannabis oils/tinctures intended for oral ingestion,
cannabis-infused food and beverage products, concen-
trated extracts, and topical/transdermal products),
method of administration (e.g., smoked, vaporized,
swallowed), and chemical composition (e.g., THC-
dominant, CBD-dominant, or balanced THC/CBD).
The public health ramifications of medicinal cannabis
legalization warrant considerable attention and invest-
ment. Prior studies have documented modest increases
in cannabis use at the population level following legaliza-
tion, particularly among older adults, despite a decrease
in the rate of Cannabis Use Disorder among users.
9,10
Mixed results have been observed with respect to opioid-
sparing effects of medicinal cannabis legalization.
11–14
Epidemiological studies indicate that motor vehicle ac-
cidents and emergency department (ED) visits have in-
creased within states that have legalized cannabis,
although the relatedness of cannabis legalization to
these changes continues to be debated.
15,16
Importantly
though, the impact of medicinal cannabis legaliza-
tion at the level of individual cannabis users is poorly
understood.
Observational research methods are ideally suited to
evaluate the health effects of medicinal cannabis use
broadly, and provide a pathway for identifying specific
health conditions and/or cannabis product characteris-
tics that warrant additional study through traditional
drug development approaches (i.e., randomized, con-
trolled trials).
17,18
Prior studies have examined the health
and demographic characteristics of medicinal cannabis
users, and/or described cannabis product selection or
use behaviors among medicinal cannabis users,
19–23
but
have lacked an adequate control group. The aim of the
present study was to compare a large convenience sample
of medicinal cannabis users to a control group of individ-
uals considering medicinal cannabis use on self-reported
measures of health. Additional prospective, longitudinal
comparisons within a subsample of cannabis users and
controls evaluated the impact of initiation, cessation,
and maintenance of medicinal cannabis use on standard-
ized health measures.
Methods
Research setting
This study was conducted by the Realm of Caring
Foundation (Colorado Springs, CO), a nonprofit orga-
nization dedicated to therapeutic cannabis research
and education, in collaboration with the Johns Hopkins
University School of Medicine (Baltimore, MD). The
Realm of Caring Foundation is a resource for those
seeking information related to the use of cannabis
for therapeutic purposes. Participants were recruited
from the Realm of Caring Foundation patient registry
and social media posts made by the organization.
These participants included both those who were al-
ready using a cannabis product and those considering
initiation of medicinal cannabis product use. Partici-
pants completed assessments through web-based sur-
veys (Qualtrics, Provo, UT). The study was approved
by the Johns Hopkins University IRB and informed
consent was obtained as part of the survey.
Participants
Participants (n=1276) were enrolled between April
2016 and February 2018. Of these, 524 were adult pa-
tients who used cannabis for medicinal purposes and
284 were adult caregivers of children or dependent
adults who used cannabis for medicinal purposes
HEALTH OF MEDICINAL CANNABIS USERS VERSUS CONTROLS 549
(Cannabis Users; n=808). The control group consisted
of 271 adult patients who were considering, but had not
yet initiated therapeutic use of cannabis, and 197 adult
caregivers who were considering therapeutic use of
cannabis for a dependent child or adult patient (Con-
trols; n=468). All participants self-reported that they
or their dependent patient had a diagnosed health con-
dition at the time of the baseline assessment. Note that
we differentially refer to participants (those who com-
pleted the study assessments) and patients (individuals
with health conditions) throughout the article.
Study measures
Participants completed a web-based survey that mea-
sured several content areas. Adult patients who were
capable self-reported all information. Caregivers com-
pleted study assessments based on observations of the
dependent patient, either adult or child, under their
care. Demographic information included the age, sex,
race/ethnicity, place of residence, marital status, and
highest level of education completed (limited to pa-
tients age 18 and over) of the patient. The primary
diagnosed health condition for which the patient was
using, or considering medicinal cannabis use, was
recorded. Daily dose, frequency of use, and route of
administration were recorded, to the extent possible,
for current prescription medication, over-the-counter
(OTC) medication, and cannabis products. Partici-
pants reported past-month outpatient health care vis-
its, ED visits, and hospital admissions, as well as
past-month sick days taken from work/school. Vali-
dated assessments were used to assess past-month
quality of life (World Health Organization Quality-
of-Life assessment; score-range: 1–5 for individual items
and 4–20 for composite scores; WHOQOL-BREF
24
),
pain (Numeric Pain Rating Scale; score-range: 0–10;
NPRS
25
), anxiety and depression (Hospital Anxiety
and Depression Scale; score-range: 0–21; HADS
26
),
and sleep (Pittsburgh Sleep Quality Index
27
[PSQI])
for adults; score-range: 0–21; Children’s Sleep Habits
Questionnaire-Abbreviated
28,29
(CSHQ-A) for children;
score-range: 22–110.
a
Participants who completed the
survey each month were entered into a raffle to win
one of twenty $50 gift cards.
Following baseline survey completion, participants
were prompted through e-mail to complete follow-up
assessments at 3-month intervals. Approximately
one-third of participants completed at least one follow-
up assessment (32.6%) at an average of 284 days
following baseline. On average, these participants
completed 1.8 assessments (median =1).
Data analyses
Patients were classified as Cannabis Users or Controls
based on self- or caregiver-reported current cannabis
use at baseline. There were no differences in study
findings when controlling for self-reported versus
caregiver report, therefore results are presented with-
out categorizing by data source. Descriptive statistics
were used to summarize patient demographics, pri-
mary health condition, and cannabis use characteris-
tics. Independent-samples t-tests and chi-square tests
of independence were used to examine differences be-
tween Cannabis Users and Controls for continuous
and categorical variables, respectively. For count var-
iables (i.e., medication use, outpatient visits, ED visits,
hospital admissions, sick days from work/school), neg-
ative binomial regressions were conducted. The Benja-
mini/Hochberg procedure
30
was used to control Type
I error associated with multiple comparisons. All results
remained significant after controlling for the false dis-
covery rate. Longitudinal data (all completed follow-
up assessments) were analyzed using linear mixed
effects model parameterizing a between- and within-
person effect of medicinal cannabis use on health
symptoms
31
as well as accounting for the effect of
time independent of medicinal cannabis use status
(see Supplementary Materials for additional details
about this methodology). These models differentiated
and tested the (1) relation of the average prevalence of
medicinal cannabis use reported throughout the ana-
lyzed period (between-subject effects) and (2) the re-
lation of time-specific deviations in medicinal
cannabis use on health symptoms (e.g., initiation or
cessation of use; within-subject effects). Longitudinal
analysis of CSHQ-A scores was not conducted due
to the low number and density of follow-up assess-
ments for patients under age 18 (n=114 follow-ups
from 77 participants) as well as the infrequent report
of cannabis cessation among children in the Cannabis
User group (n=3). Inclusion of patient demographic
(age, gender, race) and assessment (self-report vs. ob-
server report) covariates in mixed effects model did
not alter the pattern of findings or their significance.
All models were conducted in Rstatistical language
using the nlme package.
32
a
Clinical cutoffs by scale: HADS score of 8 or higher is associated with clinical
diagnosis; PSQI score of 5 or higher indicates significant sleep disturbance; there
are no widely accepted clinical cutoffs for the WHOQOL-BREF, NPRS, or CSHQ-A.
550 SCHLIENZ ET AL.
Results
Patient characteristics
Cannabis Users and Controls were similar on major de-
mographic characteristics (Table 1). Patients were pre-
dominantly Caucasian (79%), female (63%), and most
patients age 18 or older had a greater than high school
education. Cannabis Users were significantly older than
Controls [t(1274) =2.31, p<0.05], with a mean age of
38 versus 35 years, respectively, and were more likely
to report a history of nontherapeutic cannabis use (e.g.,
past-month nontherapeutic cannabis use was 10% vs.
5%, respectively).
Primary health condition
The primary self-reported diagnosed health condition
for which participants used cannabis, or considered
cannabis use, was categorized into one of seven broad
health categories (Table 2) due to the incredible diver-
sity of diagnosed health conditions reported by study
participants. Cannabis Users and Controls did not sig-
nificantly differ with respect to type of primary health
condition (w
2
[6, n=1274] =7.77, p=0.35). The most
frequently endorsed health conditions were neurologi-
cal (e.g., epilepsy, multiple sclerosis), chronic pain
(e.g., fibromyalgia, chronic back pain), and psychiatric
(e.g., anxiety, depression, post-traumatic stress disor-
der) disorders.
Cannabis use characteristics: product
recommendations, type, and dose
Among Cannabis Users, 27% reported that a physician
explicitly recommended cannabis use; 45% said that a
physician did not recommend use, and 28% provided
no response. Cannabis use was reported to be a first-
line therapy for the primary health condition among
11%, a second-line therapy for 18%, an adjunctive ther-
apy for 39%, and a treatment of last resort for 29% of
Cannabis Users (3% did not answer).
Fifty-eight percent of patients used CBD-dominant
products. By comparison, THC-dominant products
were used by 13%, balanced THC/CBD products by
5%, and products in which the highest concentration
wasaminorcannabinoid,suchascannabigerol(CBG)
or cannabinol (CBN), by 3% of Cannabis Users. Many
participants (21%) did not know or did not specify the
chemotype of the cannabis products they used.
Cannabis tinctures or oils intended for oral inges-
tion were the most commonly reported cannabis for-
mulations (47%), followed by dried cannabis flowers
(9%), ‘‘edibles’’ (8%), concentrates (3%), and other for-
mulations such as topicals or suppositories (3%).
Thirty-one percent of respondents did not report the
formulation of cannabis product they most often
used. Variability in product type, formulation, method
of use, and lack of standard dose units, packaging, and
labeling made concise summarization of dosing diffi-
cult. Certificates of analysis were obtained from manu-
facturers that enabled daily CBD and THC dose
calculations for 353 patients taking specific oral canna-
bis products. Among those participants, the mean total
daily CBD dose was 79 mg (median =40 mg; range =1–
1050 mg) and the mean total daily THC dose was 3 mg
(median =1.4 mg; range =0.1–40.3 mg). Adjusted for
body weight, the mean total daily CBD dose was
1.4 mg/kg (median =0.6 mg/kg; range =0.01–15.7 mg/kg)
Table 1. Participant Demographics
Cannabis users
(n=808)
Controls
(n=468) p
Age
Mean (SD) 38 (20) 35 (21) <0.05
Range; n(%) below age 18 1–86; 175 (22) 1–82; 136 (29)
Sex, n(%)
Male 298 (37) 177 (38) 0.71
Female 510 (63) 291 (62)
Race, n(%)
Caucasian 637 (79) 372 (79) 0.48
African American 16 (2) 18 (4)
Hispanic/Latino 38 (5) 27 (6)
Other 75 (9) 43 (9)
Not reported 42 (5) 11 (2)
Education (among age ‡18), n(%)
High school or less 106 (17) 68 (20) 0.05
Some college 133 (21) 78 (23)
Undergraduate degree 183 (29) 87 (26)
Graduate degree 123 (19) 56 (17)
Trade/technical training 51 (8) 30 (9)
Not reported 37 (6) 13 (4)
Nontherapeutic cannabis use, n(%)
Lifetime 250 (31) 113 (24) 0.01
Past year 111 (14) 42 (9) 0.01
Past month 79 (10) 24 (5) 0.005
SD, standard deviation.
Table 2. Primary Medical Condition for Which Participants
Were or Were Not Considering Use of Cannabis
Cannabis users
(n=808)
Controls
(n=468) p
Primary medical condition 0.35
Neurological, n(%) 307 (38) 170 (36) —
Chronic pain, n(%) 204 (25) 108 (23) —
Neuropsychiatric, n(%) 146 (18) 94 (20) —
Autoimmune, n(%) 75 (9) 46 (10) —
Cancer, n(%) 59 (7) 33 (7) —
Insomnia, n(%) 6 (1) 10 (2) —
Other, n(%) 11 (2) 7 (1) —
HEALTH OF MEDICINAL CANNABIS USERS VERSUS CONTROLS 551
and the mean total daily THC dose was 0.05 mg/kg
(median =0.02 mg/kg; range =<0.01–0.6 mg/kg).
Baseline health symptoms
Cannabis Users had significantly better symptoms on
most self-reported health assessments compared with
Controls at baseline (Table 3).
Quality of life. On the WHOQOL-BREF, Cannabis
Users reported greater quality of life (QOL) [t(1054) =
4.19, p<0.001] and perceived health satisfaction
[t(1045) =4.14, p<0.001], and had significantly higher
composite domain scores for physical health [t(1045) =
3.52, p<0.001], psychological health [t(1045) =4.87,
p<0.001], and social relationships [t(1025) =3.05,
p<0.01], but exhibited comparable environmental health
scores compared with Controls [t(1060) =1.36, p=0.18].
Pain. Compared with Controls, Cannabis Users
reported significantly lower average pain in the past
month on the NPRS [t(1150) =2.34, p<0.05], but did
not differ on ratings of worst pain in the past month
[t(11143) =1.33, p=0.18].
Anxiety and depression. Cannabis Users had signifi-
cantly lower scores on the Anxiety [t(1151) =4.38,
p<0.001] and Depression [t(1210) =5.77, p<0.001]
subscales of the HADS compared with Controls.
Sleep. As assessed by the CSHQ, caregiver reports in-
dicated that Cannabis Users under age 18 had better
overall sleep habits [t(224) =2.90, p<0.01], faster
sleep onset [t(316) =4.91, p<0.001], less frequent
night awakenings [t(293) =2.99, p<0.01], and fewer
parasomnias [t(267) =3.12, p<0.01] compared with
Controlsunderage18.AsassessedbythePSQI,adult
Cannabis Users had greater sleep quality [t(938) =3.96,
p<0.001], shorter sleep latency [t(954) =3.29, p<0.01],
longer sleep duration [t(954) =2.28, p<0.05], fewer
sleep disturbances [t(951) =2.77, p<0.01], and a
Table 3. Group Comparison on Baseline General Health Outcomes
Cannabis user mean (SD) [n] Controls mean (SD) [n]pCohen’s d
WHOQOL-BREF
a
Quality-of-life rating 3.5 (1.2) [674] 3.2 (1.2) [382] <0.001 0.25
Health satisfaction rating 2.4 (1.1) [669] 2.1 (1.0) [378] <0.001 0.29
Physical health domain 12.1 (3.8) [671] 11.2 (3.6) [376] <0.001 0.24
Psychological domain 13.3 (3.3) [670] 12.2 (3.3) [377] <0.001 0.33
Social relationships domain 13.3 (4.0) [656] 12.5 (4.3) [371] <0.01 0.19
Environment domain 15.0 (3.2) [678] 14.8 (3.0) [384] 0.18 0.06
NPRS
a
Average pain 3.9 (2.9) [742] 4.3 (3.0) [410] <0.01 0.14
Worst pain 5.8 (3.6) [738] 6.1 (3.5) [407] 0.18 0.08
HADS
a
———
Anxiety subscale 9.2 (5.2) [730] 10.5 (5.1) [423] <0.001 0.25
Depression Subscale 6.7 (4.8) [771] 8.4 (5.1) [441] <0.001 0.34
CSHQ (child sleep)
a
———
Total score 49.9 (10.6) [129] 54.3 (11.8) [97] <0.01 0.39
Bedtime resistance 11.4 (4.8) [172] 12.3 (5.1) [142] 0.08 0.18
Sleep onset delay 2.5 (1.0) [177] 3.1 (1.2) [141] <0.001 0.54
Sleep duration 2.5 (1.3) [178] 2.6 (1.4) [142] 0.73 0.07
Sleep anxiety 6.8 (3.6) [162] 7.1 (3.7) [131] 0.47 0.08
Night wakenings 7.1 (2.5) [163] 8.1 (2.9) [132] <0.01 0.37
Parasomnias 6.7 (2.2) [153] 7.7 (2.7) [116] <0.01 0.41
Sleep disordered breathing 2.0 (1.0) [177] 2.1 (1.2) [141] 0.48 0.09
Daytime sleepiness 9.4 (2.5) [178] 9.9 (3.1) [141] 0.08 0.18
PSQI (adult sleep)
a
———
Global score 8.9 (4.2) [501] 9.9 (4.2) [259] <0.01 0.24
Subjective sleep quality 1.5 (0.9) [618] 1.7 (0.9) [322] <0.001 0.22
Sleep latency 1.6 (1.1) [630] 1.8 (1.0) [326] <0.01 0.19
Sleep duration 0.9 (1.1) [630] 1.1 (1.1) [326] <0.05 0.18
Habitual sleep efficiency 1.0 (1.2) [520] 1.1 (1.3) [273] 0.29 0.08
Sleep disturbances 1.8 (0.6) [628] 1.9 (0.6) [325] <0.01 0.17
Use of sleep medication 1.1 (1.4) [624] 1.2 (1.4) [317] 0.44 0.07
Daytime dysfunction 1.2 (0.7) [613] 1.1 (0.7) [316] 0.17 0.14
a
For the WHOQOL-BREF, higher scores indicate better outcomes, for all other measures, lower scores indicate better outcomes.
CSHQ, Children’s Sleep Habits Questionnaire; HADS, Hospital Anxiety and Depression Scale; NPRS, Numeric Pain Rating Scale; PSQI, Pittsburgh Sleep
Quality Index; WHOQOL-BREF, World Health Organization Quality of Life-BREF.
552 SCHLIENZ ET AL.
significantly better PSQI Global Sleep Score compared
with adult Controls [t(758) =3.03, p<0.01].
Medications, health care utilization, and sick days.
Results for all negative binomial count data appear in
Table 4 and distribution of responses in Figure 1. Can-
nabis Users reported 14% fewer current prescription
medications (95% confidence interval [CI]: 0.77–
0.96), 39% fewer past-month ED visits (95% CI:
0.44–0.84), and 46% fewer hospital admissions (95%
CI: 0.34–0.87) than the Control group. Groups did
not significantly differ in the number of OTC medica-
tions, past-month outpatient health care visits, or past-
month sick days taken from work/school.
Longitudinal health symptoms
Raw data for primary health symptoms at baseline and
follow-up by medicinal cannabis use status are plotted
in Figure 2 (see Supplementary Materials for marginal
mean plots and sensitivity analyses evaluating alterna-
tive parameterizations). Consistent with the baseline
analyses, significant between-person effects of medici-
nal cannabis use (i.e., average prevalence of medicinal
cannabis use reported throughout the analyzed period)
were observed for QOL (b=0.35, p<0.001), perceived
health satisfaction (b=0.35, p<0.001), past-month av-
erage pain (b=0.47, p<0.05), Anxiety (b=1.58,
p<0.001), and Depression (b=1.78, p<0.001) sub-
scales of the HADS, and PSQI Global Sleep Score
(b=1.15, p<0.01). These effects reflected better
health scores (e.g., lower anxiety) for individuals
reporting medicinal cannabis use, on average, across
the reported period (i.e., averaging medicinal cannabis
exposure over time).
Significant within-person effects of medicinal cannabis
use (i.e., association of time-specific deviations in medic-
inal cannabis use such as initiation or cessation with
health symptoms) were also observed for QOL (b=0.22,
p<0.01), perceived health satisfaction (b=0.23, p<0.01),
past-month average pain (b=0.42, p<0.05), past-
month worst pain (b=0.46, p<0.05), and the Anxi-
ety (b=1.56, p<0.001) and Depression (b=1.87,
p<0.001) subscales of the HADS. These within-
person effects each reflected improved health scores
during specific assessment periods in which medicinal
cannabis was reported compared with assessment peri-
ods in which it was not reported for individual partic-
ipants (i.e., indicating that initiation of medicinal
cannabis use, on average, was associated with improved
symptoms and cessation of medicinal cannabis use, on
average, was associated with worse symptoms on these
variables).
A sensitivity analysis was conducted to determine if
missing data contributed to the observed results. No sig-
nificant differences between participants providing follow-
up data and those without were observed in age ( p=0.99),
gender ( p=0.54), race ( p=0.52), report status (self vs. ob-
server) ( p=0.58), or any of the global health measures an-
alyzed ( pvalues >0.16). Participants reporting current
medicinal cannabis use at baseline were more likely to
provide a follow-up assessment (odds ratio [OR] =1.40,
p=0.008). Sensitivity models in which only participants
with follow-up data were analyzed found between- and
within-subject associations in the same direction and sig-
nificance as the primary models are reported above.
Qualitative information was coded from 67 partici-
pants who reported discontinuation at some point
during the longitudinal period. Over half (55%) cited
financial concerns as a reason for discontinuation.
Other reasons for discontinuation included legal/
employment restrictions (16%), no benefit (13%), and
negative health consequences (13%).
Discussion
Decisions surrounding medicinal cannabis use are
challenging for both clinicians and patients due to
the diversity of products, abuse liability of cannabis,
potential product contamination or label inaccuracies,
complicated regulatory structure, and dearth of con-
trolled clinical trials on defined products for targeted
health indications.
1
In this study, Cannabis Users
reported better health and QOL, and less health care
Table 4. Group Prediction of Medication Use, Past-Month
Health Care Utilization, and Sick Days
Dependent variable, (n) Exp(B) 95% CI
Likelihood
ratio w
2
Predictor
Prescription medications, (n=774) — — 7.71
a
Group (cannabis users) 0.86
a
0.77–0.96 —
Over-the-counter medications, (n=763) — — 0.74
Group (cannabis users) 1.06 0.93–1.22 —
Outpatient visits, (n=731) — — 0.11
Group (cannabis users) 1.03 0.89–1.19 —
Emergency department visits, (n=307) — — 9.31
a
Group (cannabis users) 0.61
a
0.44–0.84 —
Hospital admissions, (n=180) — — 6.35
b
Group (cannabis users) 0.54
b
0.34–0.87 —
Sick days from school/work, (n=675) — — 1.86
Group (cannabis users) 0.83 0.63–1.09 —
a
p<0.01,
b
p<0.05.
CI, confidence interval.
HEALTH OF MEDICINAL CANNABIS USERS VERSUS CONTROLS 553
utilization compared with largely comparable Controls.
The observed clinical benefit associated with medicinal
cannabis use in this study is consistent with other obser-
vational studies.
19,23,33–35
That only 27% of participants
reported that a physician explicitly recommended me-
dicinal cannabis use is somewhat concerning. Increased
physician involvement in medicinal cannabis decision
making is desirable for patient safety as well as for
monitoring, recording, and disseminating clinical out-
comes. This study extends prior research by including a
FIG. 1. Distribution of medication use and health care utilization by group assignment at baseline.
554 SCHLIENZ ET AL.
FIG. 2. Observed values for health outcomes at baseline and follow-up by medicinal cannabis use status.
Plotted are values for the Control group who initiated cannabis use in follow-up (solid circle/solid line),
Cannabis User group who continued use in follow-up (solid square/solid line), Control group who did not
initiate use in follow-up (open circle/dotted line), and Cannabis Group that discontinued use in follow-up
(open square/dotted line). For baseline groupings, individuals who did not provide follow-up data were
treated as belonging in the nonuse group for presentation purposes. Y-axis legends reflect total scale range.
Dotted line on HADS-A and HADS-D represent clinical cutoff for patient follow-up. Individual sample sizes
range from 22 to 523 depending on the time point, group, and assessment depicted. Error bars are standard
error. HADS, Hospital Anxiety and Depression Scale.
555
large sample size, both child and adult patients, only
individuals who self-reported a diagnosed health prob-
lem, assessment of multiple health domains, and a con-
trol group.
CBD-dominant products were used at a higher rate
relative to THC-dominant products, and doses of
CBD (mean 79 mg; 1.4 mg/kg) and THC (mean
3 mg; 0.5 mg/kg) used tended to be lower than what
hasbeenusedinpriorhumanlaboratorystudies
and clinical trials. For comparison, the recommended
maintenancedosage(listedonthepackageinsert)for
Epidiolex in the treatment of rare seizure disorders
is 10–20 mg/kg/day. The recommended starting dose
of dronabinol (listed on the package insert) is
5 mg/day for the treatment of anorexia in adults
with HIV/AIDS and is 20–30 mg/day for adults who
have nausea or emesis associated with chemotherapy.
Of note, most participants in this study were using
cannabis for health conditions other than the FDA-
approved uses of CBD or THC, and for which effec-
tive doses have not been determined in controlled
clinical trials.
An additional contribution of this study was the
evaluation of prospective changes in health symptoms
following initiation, cessation, or maintenance of me-
dicinal cannabis product use. These analyses indicated
significant within-person effects, in addition to the
between-person effects observed between Cannabis
Users and Controls at baseline. Within-person change
reflected the observation that initiation of medicinal
cannabis use resulted in significant increases in QOL
and health satisfaction as well as decreases in anxiety
and depression that were comparable in magnitude
to the difference between Cannabis Users and Controls
observed at baseline. Similarly, maintenance on me-
dicinal cannabis in the Cannabis User group resulted
in sustained improvements on these measures,
whereas cessation of use often resulted in a decrease
in health and QOL indicating that stopping medicinal
cannabis use was associated with a diminishing or re-
bound of effect. Notably, pain and sleep showed less
robust impacts when evaluated in this longitudinal
setting. This outcome is not entirely surprising given
that the cross-sectional comparisons for these mea-
sures made at baseline were consistent with smaller
magnitude differences. Additionally, evidence for the
opioid-sparing effects of cannabisproductsonmod-
erate or severe chronic pain have been mixed, as
noted in the introduction. It is also possible that the
magnitude (and potential direction) of these effects
will vary depending on the chronic health condition
evaluated (e.g., see evidence of specific sleep-related
motives for medicinal cannabis use among individuals
with PTSD
36
).
Several methodological limitations must be ac-
knowledged. The study was conducted with a conve-
nience sample of individuals registered with the
Realm of Caring Foundation who were willing to com-
plete a research assessment; thus, this sample may not
be representative of medicinal cannabis users broadly.
In addition, biases may be represented in both groups.
Specifically, individuals in the cannabis group likely al-
ready observed a benefit from use and continued to
use medicinal cannabis products for this reason. On
the other hand, individuals in the control group
were those seeking information regarding medicinal
cannabis products, and therefore have both unre-
solved symptomatology and at least some belief that
cannabis may improve those symptoms. High rates
of missing data were also observed during the pro-
spective portion of the study. This attrition is likely at-
tributable to study-related factors, including the
relatively modest incentives (i.e., probabilistic pay-
ments) and the exclusive use of reminder emails to en-
courage compliance. Sensitivity analyses indicated that
individuals with missing data did not significantly differ
on demographic factors or the health-related symptoms
analyzed and evaluation of longitudinal health symptoms
in a completion-only group revealed similar findings.
Nevertheless, future efforts to improve retention should
be explored (e.g., closer monitoring or an escalating incen-
tive schedule for long-term adherence). Last, the effect sizes
observed were generally small in magnitude (most Cohen’s
d0.20-to-0.30). The clinical significance of these differ-
ences are difficult to assess due to reliance on self-report
versus clinician assessment or objective measures of
health, the heterogeneity of the sample with respect to
health condition, the type of cannabis products being
used, and the manner in which products were used (dos-
ing regimen as well as physician supervision of use). It is
important that additional research on the magnitude and
clinical viability of these effects be conducted in more con-
trolled clinical settings in which known and consistent
dosing and product types are utilized.
The key finding of this study is that medicinal can-
nabis use was associated with more positive ratings of
health and QOL, assessed across multiple domains.
Prospective analyses found that Controls showed im-
provement in health and QOL if they initiated medic-
inal cannabis use, and that Cannabis Users showed
556 SCHLIENZ ET AL.
diminished health and QOL if they stopped cannabis
use. Because of this, we hypothesize that these group
differences were related to the use of medicinal canna-
bis products. That said, due to the aforementioned
limitations, the results of this study do not provide de-
finitive evidence that cannabis is an effective thera-
peutic. Rather, the results clearly indicate that additional
research should be conducted to further evaluate the ob-
served data in more targeted, representative subpopula-
tions of cannabis users. Such studies can be used to
identify specific health conditions, product types, and
doses that are appropriate for evaluation in controlled clin-
ical trials. Although the current design included a control
group to improve interpretation, future observational
studies should consider the use of Ecological Momentary
Assessment technology (i.e., repeated sampling of behavior
in real time) and/or corroboration of patient self-reports
with collateral data from additional sources such as elec-
tronic medical records or direct reporting from the physi-
cian or other health professional caring for the patient.
Acknowledgments
The authors wish to thank the study participants for
contributing their time and the staff at the Realm of
Caring Foundation and Johns Hopkins University
who contributed to this project.
Author Disclosure Statement
Dr. Bonn-Miller is an employee of Canopy Growth
Corporation, during which time he has received stock
options. He serves on the Board of Directors for Aus-
Cann Group Holdings Limited, was a prior employee
of Zynerba Pharmaceuticals, and he has received con-
sulting fees from Tilray Inc. Dr. Vandrey has received
compensation as a consultant or advisory board mem-
ber from Zynerba Pharmaceuticals, Canopy Health
Innovations Inc., and FSD Pharma.
Funding Information
This study was funded by the Realm of Caring Founda-
tion. Additional funding was provided by NIH/NIDA
Training Grant T32-DA07209 (support for Drs. Schlienz
and Strickland).
Supplementary Material
Supplementary Data
Supplementary Figure S1
Supplementary Figure S2
Supplementary Figure S3
References
1. Vandrey R. The cannabis conundrum: steering policy and medicine with
insufficient data. Int Rev Psychiatry. 2018;30:181–182.
2. ProCon. Number of legal medical marijuana patients in the U.S. as of May
2018, by state. 2018; https://www.statista.com/statistics/585154/us-legal-
medical-marijuana-patients-state/. Accessed April 3, 2019.
3. Realm of Caring. Qualifying Conditions for a Medical Marijuana Card by
State. 2019; https://rebrand.ly/roc-state-med-conditions. Accessed April
9, 2019.
4. Radwan MM, Elsohly MA, Slade D, et al. Biologically active cannabinoids
from high-potency Cannabis sativa. J Nat Prod. 2009;72:906–911.
5. Morales P, Hurst DP, Reggio PH. Molecular targets of the phytocannabi-
noids: a complex picture. Prog Chem Org Nat Prod 2017;103:103–131.
6. Mechoulam R, Gaoni Y. The absolute configuration of delta-1-
tetrahydrocannabinol, the major active constituent of hashish. Tetrahe-
dron Lett. 1967;12:1109–1111.
7. Bergamaschi MM, Queiroz RH, Zuardi AW, et al. Safety and side effects
of cannabidiol, a Cannabis sativa constituent. Curr Drug Saf. 2011;6:
237–249.
8. Schoedel KA, Szeto I, Setnik B, et al. Abuse potential assessment of
cannabidiol (CBD) in recreational polydrug users: a randomized,
double-blind, controlled trial. Epilepsy Behav. 2018;88:162–171.
9. Hasin DS, Sarvet AL, Cerda M, et al. US adult illicit cannabis use, cannabis
use disorder, and medical marijuana laws: 1991–1992 to 2012–2013.
JAMA Psychiatry. 2017;74:579–588.
10. Hasin DS, Saha TD, Kerridge BT, et al. Prevalence of marijuana use
disorders in the United States between 2001–2002 and 2012–2013. JAMA
Psychiatry. 2015;72:1235–1242.
11. Shover CL, Davis CS, Gordon SC, et al. Association between medical
cannabis laws and opioid overdose mortality has reversed over time. Proc
Natl Acad Sci U S A. 2019;116:12624–12626.
12. Bachhuber MA, Saloner B, Cunningham CO, et al. Medical cannabis laws
and opioid analgesic overdose mortality in the United States, 1999–2010.
JAMA Intern Med. 2014;174:1668–1673.
13. Campbell G, Hall WD, Peacock A, et al. Effect of cannabis use in
people with chronic non-cancer pain prescribed opioids: findings
from a 4-year prospective cohort study. Lancet Public Health. 2018;3:
e341–e350.
14. Liang D, Bao Y, Wallace M, et al. Medical cannabis legalization and opioid
prescriptions: evidence on US Medicaid enrollees during 1993–2014.
Addiction. 2018;113:2060–2070.
15. Salomonsen-Sautel S, Min SJ, Sakai JT, et al. Trends in fatal motor vehicle
crashes before and after marijuana commercialization in Colorado. Drug
Alcohol Depend. 2014;140:137–144.
16. Kim HS, Hall KE, Genco EK, et al. Marijuana tourism and emergency
department visits in colorado. N Engl J Med. 2016;374:797–798.
17. Yang W, Zilov A, Soewondo P, et al. Observational studies: going beyond
the boundaries of randomized controlled trials. Diabetes Res Clin Pract.
2010;88 Suppl 1:S3–S9.
18. Dreyer NA, Tunis SR, Berger M, et al. Why observational studies should be
among the tools used in comparative effectiveness research. Health Aff.
2010;29:1818–1825.
19. Bonn-Miller MO, Boden MT, Bucossi MM, et al. Self-reported cannabis use
characteristics, patterns and helpfulness among medical cannabis users.
Am J Drug Alcohol Abuse. 2014;40:23–30.
20. Cranford JA, Arnedt JT, Conroy DA, et al. Prevalence and correlates of
sleep-related problems in adults receiving medical cannabis for chronic
pain. Drug Alcohol Depend. 2017;180:227–233.
21. Davis AK, Walton MA, Bohnert KM, et al. Factors associated with alcohol
consumption among medical cannabis patients with chronic pain. Addict
Behav. 2018;77:166–171.
22. Haug NA, Padula CB, Sottile JE, et al. Cannabis use patterns and motives: a
comparison of younger, middle-aged, and older medical cannabis dis-
pensary patients. Addict Behav. 2017;72:14–20.
23. Suraev A, Lintzeris N, Stuart J, et al. Composition and use of cannabis
extracts for childhood epilepsy in the Australian community. Sci Rep.
2018;8:10154.
24. The WHOQOL Group. Development of the World Health Organization
WHOQOL-BREF quality of life assessment. Psychol Med. 1998;28:551–558.
25. McCaffery M, Beebe A. Pain: clinical manual for nursing practice. C.V.
Mosby Company: St. Louis, MO, 1989.
HEALTH OF MEDICINAL CANNABIS USERS VERSUS CONTROLS 557
26. Zigmond AS, Snaith RP. The hospital anxiety and depression scale. Acta
Psychiatr Scand. 1983;67:361–370.
27. Buysse DJ, Reynolds CF, Monk TH, et al. The Pittsburgh Sleep Quality
Index: a new instrument for psychiatric practice and research. Psychiatry
Res. 1989;28:193–213.
28. Owens JA, Spirito A, McGuinn M. The Children’s Sleep Habits Question-
naire (CSHQ): psychometric properties of a survey instrument for school-
aged children. Sleep. 2000;23:1043–1051.
29. Hartman AG, Terhorst L, Little N, et al. Uncovering sleep in young males
with Duchenne muscular dystrophy. Eur J Paediatr Neurol. 2020;S1090-
3798(20)30043-X.DOI: 10.1016/j.ejpn.2020.02.012.
30. Benjamini Y, Hochberg Y. Controlling the false discovery rate: a practical
and powerful approach to multiple testing. J Royal Statistic Soc B
(Methodological). 1995;57:289–300.
31. Wang LP, Maxwell SE. On disaggregating between-person and within-
person effects with longitudinal data using multilevel models. Psychol
Methods. 2015;20:63–83.
32. Pinheiro J, Bates D, DebRoy S, et al. Package ‘‘nlme.’’ Linear and Nonlinear
Mixed Effects Models, version, 3-1. 2017.
33. Perron BE, Bohnert K, Perone AK, et al. Use of prescription pain medica-
tions among medical cannabis patients: comparisons of pain levels,
functioning, and patterns of alcohol and other drug use. J Stud Alcohol
Drugs. 2015;76:406–413.
34. Bar-Lev Schleider L, Mechoulam R, Saban N, et al. Real life experience of
medical cannabis treatment in autism: analysis of safety and efficacy. Sci
Rep. 2019;9:200.
35. Gruber SA, Sagar KA, Dahlgren MK, et al. The grass might be greener:
medical marijuana patients exhibit altered brain activity and improved
executive function after 3 months of treatment. Front Pharmacol.
2017;8:983.
36. Bonn-Miller MO, Babson KA, Vandrey R. Using cannabis to help you sleep:
heightened frequency of medical cannabis use among those with PTSD.
Drug Alcohol Depend. 2014;136:162–165.
Cite this article as: Schlienz NJ, Scalsky R, Martin EL, Jackson H,
Munson J, Strickland JC, Bonn-Miller MO, Loflin M, Vandrey R (2021)
A cross-sectional and prospective comparison of medicinal cannabis
users and controls on self-reported health, Cannabis and Cannabinoid
Research 6:6, 548–558, DOI: 10.1089/can.2019.0096.
Abbreviations Used
CBD ¼cannabidiol
CI ¼confidence interval
CSHQ-A ¼Children’s Sleep Habits Questionnaire-Abbreviated
ED ¼emergency department
FDA ¼Food and Drug Administration
HADS ¼Hospital Anxiety and Depression Scale
NPRS ¼Numeric Pain Rating Scale
PSQI ¼Pittsburgh Sleep Quality Index
QOL ¼quality of life
RR ¼rate ratio
SD ¼standard deviation
THC ¼tetrahydrocannabinol
WHOQOL-BREF ¼World Health Organization Quality of Life-BREF
558 SCHLIENZ ET AL.