ArticlePDF Available

The Association between Cannabis Product Characteristics and Symptom Relief

Authors:

Abstract and Figures

Federal barriers and logistical challenges have hindered measurement of the real time effects from the types of cannabis products used medically by millions of patients in vivo. Between 06/06/2016 and 03/05/2018, 3,341 people completed 19,910 self- administrated cannabis sessions using the mobile device software, ReleafApp to record: type of cannabis product (dried whole natural Cannabis flower, concentrate, edible, tincture, topical), combustion method (joint, pipe, vaporization), Cannabis subspecies (C. indica and C. sativa), and major cannabinoid contents (tetrahydrocannabinol, THC; and cannabidiol, CBD), along with real-time ratings of health symptom severity levels, prior-to and immediately following administration, and reported side effects. A fixed effects panel regression approach was used to model the within-user effects of different product characteristics. Patients showed an average symptom improvement of 3.5 (SD = 2.6) on an 11-point scale across the 27 measured symptom categories. Dried flower was the most commonly used product and generally associated with greater symptom relief than other types of products. Across product characteristics, only higher THC levels were independently associated with greater symptom relief and prevalence of positive and negative side effects. In contrast, CBD potency levels were generally not associated with significant symptom changes or experienced side effects.
Content may be subject to copyright.
1
SCIENTIFIC REPORTS | (2019) 9:2712 | https://doi.org/10.1038/s41598-019-39462-1
www.nature.com/scientificreports
The Association between Cannabis
Product Characteristics and
Symptom Relief
Sarah S. Stith, Jacob M. Vigil, Franco Brockelman, Keenan Keeling & Branden Hall
Federal barriers and logistical challenges have hindered measurement of the real time eects from
the types of cannabis products used medically by millions of patients in vivo. Between 06/06/2016 and
03/05/2018, 3,341 people completed 19,910 self- administrated cannabis sessions using the mobile
device software, ReleafApp to record: type of cannabis product (dried whole natural Cannabis ower,
concentrate, edible, tincture, topical), combustion method (joint, pipe, vaporization), Cannabis
subspecies (C. indica and C. sativa), and major cannabinoid contents (tetrahydrocannabinol, THC;
and cannabidiol, CBD), along with real-time ratings of health symptom severity levels, prior-to and
immediately following administration, and reported side eects. A xed eects panel regression
approach was used to model the within-user eects of dierent product characteristics. Patients
showed an average symptom improvement of 3.5 (SD = 2.6) on an 11-point scale across the 27
measured symptom categories. Dried ower was the most commonly used product and generally
associated with greater symptom relief than other types of products. Across product characteristics,
only higher THC levels were independently associated with greater symptom relief and prevalence of
positive and negative side eects. In contrast, CBD potency levels were generally not associated with
signicant symptom changes or experienced side eects.
Medical cannabis markets are currently being ooded with thousands of cannabis strains with unique cannabi-
noid proles1, novel, uninvestigated cannabis-derived formulates and products with little to no clinical references
or formal guidance on how fundamental characteristics of the products themselves may aect pharmacodynam-
ics2,3. Federal laws have all but prohibited the use of prospective, pragmatic, naturalistic studies with random
treatment assignment for measuring the eects of cannabis consumed in vivo. What little clinical research does
exist is mostly limited to randomized controlled trials (RCTs) using synthetic cannabinoids or low quality and
potency cannabis obtained from the federal government that is unrepresentative of the cannabis products used by
millions of people every day4,5. Contributing to further confusion are historically contradictory messages coming
from the scientic community on the true risks and benets of cannabis consumption. For example, whereas
cannabis was once oen and sometimes still is described as component cause of schizophrenia6,7, several studies
now suggest the use of medical cannabis as an eective alternative therapy to antipsychotics and for treating
schizophrenia more generally811. Contradictory eects are oen attributed to the distinction between what has
been historically interpreted as cannabisharmful, psychoactive cannabinoid, tetrahydrocannabinol (THC), oen
described as providing the ‘high’ eects versus the therapeutic, non-psychoactive potential (sometimes described
as a ‘miracle cure’ in the popular media) of cannabidiol (CBD)12. In actuality, few large-scale investigations to
date have measured the relative eects of THC and CBD consumption in real-time under naturalistic conditions
among people diagnosed with schizophrenia or any other user group.
is is the rst study to measure how fundamental characteristics of cannabis products consumed in vivo aect
immediate symptom relief and experienced side eects. We operationalize our research question using a mobile
device soware application (app). Although hundreds of cannabis-themed soware apps are available for public
use13, the ReleafApp educational soware14 is the rst app designed specically to record how the route of admin-
istration, combustion method, cannabis subspecies, and major cannabinoid contents are associated with real-time
measurements of symptom severity levels, prior to and immediately following administration of cannabis, and the
manifestation of myriad possible side eects. Despite recent advocacy for the benets of CBD over THC, the vast
majority of observational studies showing an association between patient-managed cannabis use and improvements
University of New Mexico, The Department of Psychology, Albuquerque, USA. Correspondence and requests for
materials should be addressed to J.M.V. (email: vigilj@unm.edu)
Received: 4 May 2018
Accepted: 22 January 2019
Published: xx xx xxxx
OPEN
Content courtesy of Springer Nature, terms of use apply. Rights reserved
2
SCIENTIFIC REPORTS | (2019) 9:2712 | https://doi.org/10.1038/s41598-019-39462-1
www.nature.com/scientificreports
www.nature.com/scientificreports/
in symptoms related to, for example, chronic pain15, multiple sclerosis and Parkinson’s disease16, post-traumatic
stress disorder17, and schizophrenia18 relied on public or commercially available cannabis that has been hybridized
for high THC and low CBD contents, thus suggesting that THC may be an important determinant of user outcomes.
Findings from this study are expected to contribute to guidelines for safe and eective cannabis consumption19,20,
which until now have been limited to anecdotal or retrospective reporting and ungeneralizable experiments.
Methods
Study Design. Institutional Review Board approval was obtained from the University of New Mexico for this
study and methods were performed in accordance with the approved guidelines. e preexisting anonymized data
were obtained with user informed consent through the owner of the ReleafApp, MoreBetter, Ltd., and subject to an
investigator condentiality agreement. e ReleafApp patient education and cannabis treatment management tool was
designed to track patient sessions and real-time cannabis use experiences in order to optimize the therapeutic eects
of consuming cannabis, while minimizing negative side eects. ReleafApp users voluntarily download the application
and enter information on the product they intend to consume, including type of product (whole natural dried ower,
concentrate, edible, tincture, and topical); when applicable, combustion method (joint, dry or water pipe, and vape);
plant subspecies (C. indica, C. sativa, or hybrid); and THC and CBD potency levels (percentage of total weight)21,22.
Testing of the potencies of both cannabinoids is almost universally required under U.S. medical marijuana laws and
generally reported on product labels. THC and CBD levels were capped at 35% for ower due to biological limitations
on how much THC and CBD a plant can contain. Prior to beginning a session, the patient is required to enter a neg-
ative health symptom, selected from 27 possible symptom categories, for which they are attempting to use cannabis
therapeutically. (A list of symptom categories and frequencies is available in Supplementary TableS1.)
Aer entering a symptom, patients are prompted to record a starting symptom level on a visual analogue scale
from 0 (no detectable symptom level) to10 (severe). e patient then taps the prompt on the screen to begin the
session. From that time until the patient closes the session, they can enter multiple symptom severity levels as
frequently as desired. For the current analyses, we include in our sample only patients entering starting symptoms
greater than 0 and recording at least one symptom level within 90 minutes of starting the session; we use the last
symptom level recorded within that timeframe as the ending symptom level. Our nal sample includes 19,910
sessions and 3,341 patients who recorded at least one product characteristic in the ReleafApp between 06/06/2016
and 03/05/2018. Because the entry of product characteristics is voluntary, the sample sizes used in our analyses
vary depending on which product characteristics are included. Whole natural dried Cannabis ower and con-
centrates made from the ower are the most common types of products and most likely to contain information
on the full spectrum of product characteristics. Panels A through E of Table1 show descriptive statistics for the
product characteristics recorded by the ReleafApp; specically, product type (Panel A), ower and concentrate
combustion method (Panel B), subspecies (Panel C), THC potency (Panel D), and CBD potency (Panel E).
Study Outcomes. Our main outcome is changes in symptom severity following cannabis consumption (ending
symptom level minus starting symptom level) as shown in Table1, Panel F. During a session, the patient also can report
side eects, including 12 negative side eects, 19 positive side eects, and 11 context-specic side eects, crowd-sourced
from users, dispensaries, beta testers, and app developers (Supplementary TableS2). Patients can select as many side
eects as they like, and at least one side eect was reported in 78% of sessions in our sample. We use as outcome varia-
bles whether a patient reported any side eect by category and the percent of the number of side eects available in each
of our three respective categories that a patient selected (Table1, Panel G). e most commonly reported negative side
eects are Dry Mouth (26%) and feeling Foggy (23%), the most frequent positive side eects are Relaxed (63%) and
Peaceful (54%), and the most common context-specic side eects are feeling High (37%) and irsty (27%).
Statistical Analysis. Our basic statistical model uses a least squares panel regression approach with repeated
observations (sessions) at the patient level to analyze how product characteristics aect symptom relief and side
eects. We include patient-specic xed eects to control for time-invariant user characteristics, in order to
compare how changing a product characteristic aects symptom relief and side eects for a given user rather than
comparing outcomes across users who may dier in many ways, including which products they choose to con-
sume. Because higher starting symptom levels are associated with greater symptom relief (r = 0.60), we control
for the starting symptom level in all of our regressions. Standard errors are clustered at the user level to control
for heteroskedasticity and arbitrary correlation. Because the number of observations varies substantially by prod-
uct category, we run regressions separately for each product characteristic category (product type, combustion
method, subspecies, and THC and CBD levels) as well as regressions with all product characteristics included.
In order to explore whether cannabis product characteristics dier across symptom categories in their associa-
tion with momentary symptom relief and side eect proles, we conduct sub-analyses with samples dened by the
three most frequently reported symptom categories: anxiety (16% of the sample), back pain (8%), and depression
(10%). Lastly, we explore whether side eect proles vary with product characteristics. We regress reports of any,
and the proportion of side eects selected from each side eect category (negative, positive, context-specic) on
our product characteristics using ordinary least squares for consistency across models, although our side eect
outcomes are constrained to {0,1} and [0,1]. All predicted outcomes from our regressions fall between zero and one.
Results
Table2 shows our results for the eects of product characteristics on patient symptom relief. All regressions
control for the starting symptom level, which renders the constant positive. e similar size of the coecients for
the starting symptom level and the constant mean that patients reporting symptom levels of 1 may experience
little symptom relief. However, even with a starting symptom level of just 2, users are predicted to experience
Content courtesy of Springer Nature, terms of use apply. Rights reserved
3
SCIENTIFIC REPORTS | (2019) 9:2712 | https://doi.org/10.1038/s41598-019-39462-1
www.nature.com/scientificreports
www.nature.com/scientificreports/
statistically signicant symptom relief. (e average user reports a starting symptom level of 6, SD = 2.2.) e
number of sessions, R-squared and number of users are also reported and vary across regressions, with each
regression designated by a column.
e rst column showing the eects of consuming the dierent product types on symptom relief relative to
the eects from ower suggests that ower provides more symptom relief than any other type of product. e
second column comparing C. indica and C. sativa plant sub-species to hybrid plants suggests that products from
pure indicas may increase symptom relief while sativa strains may decrease it. Combustion method does not
explain any dierence in symptom relief across products within users, as shown in Column [3]. Column [4] of
Table2 shows that whereas higher THC oers greater symptom relief, higher CBD oers no statistically signi-
cant benet. e last column of Table2 includes all product characteristics. Due to the inclusion of combustion
method, only ower and concentrate product types are included. e eect of THC becomes stronger and is the
only statistically signicant determinant of symptom relief among the product characteristics.
Figure1 shows changes in symptom severity by THC and CBD percentage category for dried natural ower,
the most popular and homogenous type of cannabis product in the sample, aer adjusting for the remainder
of the product characteristics. Regression coecients (controlling for the remaining product characteristics;
see Supplementary TableS3) showed that ower containing the middle (10–19%) and highest (20–35%) THC
potency levels was associated with greater symptom improvement than ower in the lowest THC potency cate-
gory (0–9%). As with the omnibus tests in Table2, variability in CBD levels in ower was not associated with dif-
ferences in symptom improvement. Figure2 shows adjusted changes in symptom severity by the THC percentage
Mean Std.
Dev. Minimum Maximum
Panel A: Product Type (19,910 sessions, 3,341 users)
Concentrate 0.17 0.38 0 1
Edible 0.05 0.21 0 1
Flower 0.74 0.44 0 1
Tincture 0.04 0.20 0 1
Top ica l 0.00 0.06 0 1
Panel B: Subspecies (17,197 sessions, 2,996 users)
Hybrid 0.48 0.50 0 1
C. indica 0.30 0.46 0 1
C. sativa 0.22 0.41 0 1
Panel C: Combustion Method (16,902 sessions, 2,936)
Joint 0.13 0.33 0 1
Pipe 0.43 0.49 0 1
Vap e 0.45 0.50 0 1
Panel D: THC (6,958 sessions, 1,260 users)
% THC 28.3 22.8 0 100
THC < 10% 0.16 0.36 0 1
THC 10–19% 0.29 0.45 0 1
THC 20–34% 0.36 0.48 0 1
THC 35%+0.20 0.40 0 1
Panel E: CBD (5,400 sessions, 1,123 users)
% CBD 11.6 16.0 0 100
CBD < 1% 0.25 0.43 0 1
CBD 1–9% 0.33 0.47 0 1
CBD 10–34% 0.34 0.47 0 1
CBD 35%+0.08 0.28 0 1
Panel F: Outcome and Control Variables (19,910 sessions, 3,341 users)
Symptom Change 3.5 2.6 10 9
Starting Symptom Level 6.0 2.2 1 10
Ending Symptom Level 2.4 2.2 0 10
Panel G: Side Eects (15,617 sessions, 2,757 users)
Any Negative Side Eect 0.62 0.48 0.00 1.00
% of Negative Side Eects 0.12 0.14 0.00 0.92
Any Positive Side Eect 0.95 0.23 0.00 1.00
% of Positive Side Eects 0.25 0.18 0.00 1.00
Any Context-Specic Side Eect 0.78 0.41 0.00 1.00
% of Context-Specic Side Eects 0.22 0.20 0.00 1.00
Table 1. Descriptive Statistics. Notes: Nineteen positive, twelve negative, and eleven context-specic side eects
were available for selection.
Content courtesy of Springer Nature, terms of use apply. Rights reserved
4
SCIENTIFIC REPORTS | (2019) 9:2712 | https://doi.org/10.1038/s41598-019-39462-1
www.nature.com/scientificreports
www.nature.com/scientificreports/
category of ower run separately for the three most common medical cannabis patient conditions, anxiety, back
pain, and depression. Regression coecients controlling for the remaining product characteristics showed that
only users treating depression showed greater symptom improvement from using ower in the middle and high-
est THC potency categories relative to the least potent ower. In contrast, variability in THC was not associated
with statistically signicant dierences in symptom relief for back pain or anxiety beyond its overall eect on
mean symptom improvement levels (see Supplemental TableS3).
In Table3, we present the relationship between product characteristics and side eect proles. We restrict
our analysis to only concentrates and ower to capture the relationship between dierent combustion methods
and side eects. While these methods do not explain any statistically signicant variation in symptom relief, they
may be associated with dierent side eect proles. We run our full model using any and the percent of each
category of side eects selected by the user. Concentrates showed a weaker association with positive side eects,
but do not appear to dier from ower in their association with negative or context-specic side eect report-
ing. Indica-based products are associated with a greater likelihood of reporting negative side eects and some
evidence of fewer positive and more context-specic side eects, relative to hybrid- and sativa-based products.
Outcome = Symptom Change (Ending - Starting Symptom)
(1) (2) (3) (4) (5)
Panel A: Product Type, omitted category = ower
Concentrate 0.194** 0.080
(0.076) (0.212)
Edible 0.340***
(0.105)
Tincture 0.498***
(0.117)
Top ica l 0.216
(0.355)
Panel B: Subspecies, omitted category = hybrid
C. indica 0.103** 0.057
(0.041) (0.083)
C. sativa 0.096*0.195
(0.055) (0.121)
Panel C: Combustion Method, omitted category = joint
Pipe 0.061 0.004
(0.084) (0.194)
Vap e 0.051 0.051
(0.092) (0.210)
Panel D: THC and CBD, omitted categories = THC < 10% and CBD < 1%
THC 10–19% 0.215*0.220*
(0.117) (0.134)
THC 20–34% 0.235** 0.315***
(0.112) (0.121)
THC 35%+0.252** 0.342**
(0.126) (0.166)
CBD 1–9% 0.089 0.026
(0.121) (0.126)
CBD 10–34% 0.038 0.079
(0.105) (0.092)
CBD 35%+0.222 0.241
(0.209) (0.227)
Starting Symptom Level 0.704*** 0.721*** 0.726*** 0.709*** 0.717***
(0.028) (0.031) (0.032) (0.056) (0.063)
Constant 0.588*** 0.691*** 0.719*** 0.909*** 0.850**
(0.165) (0.184) (0.212) (0.340) (0.403)
Number of sessions 19,910 17,197 16,898 4,439 3,869
R-squared 0.330 0.340 0.338 0.337 0.346
Number of users 3,341 2,996 2,936 900 787
Table 2. Eects of Product Characteristics on Symptom Relief. Notes: Regressions control for individual user
xed eects. Concentrate is relative to Flower, C. indica and C. sativa are relative to Hybrid, THC categories are
relative to THC 0–9%, CBD categories are relative to CBD 0%, and Pipe and Vape are relative to Joint. Standard
errors are clustered at the user level (shown in parentheses). ***p < 0.01, **p < 0.05, *p < 0.1.
Content courtesy of Springer Nature, terms of use apply. Rights reserved
5
SCIENTIFIC REPORTS | (2019) 9:2712 | https://doi.org/10.1038/s41598-019-39462-1
www.nature.com/scientificreports
www.nature.com/scientificreports/
Higher THC generally is associated with increased reporting of all three types of side eects. Just as with symp-
tom relief, CBD appears to have little eect on side eect reporting of any kind. ere is some evidence that
vaping is associated with decreased reporting of negative side eects relative to smoking joints. Lastly, in order to
show that a handful of very frequent ReleafApp users are not driving the results, we replicated our main results
from Table2 including only individuals who completed ten sessions or fewer, and separately, including only the
rst ve sessions for all users. THC again is the greatest predictor of symptom relief among the product charac-
teristics. (See Supplemental TableS4 for detailed results).
Discussion
Given just how common it is for cannabis patients to try dierent types of products and methods of administra-
tion23,24, it is surprising how few previous investigations have examined which fundamental characteristics of the
products consumed in vivo by millions of people daily are associated with real-time patient outcomes and expe-
rienced side eects. While RCTs may be the ‘gold standard’ for measuring the pharmacodynamics of synthetic,
standardized (usually particular symptom focused) medications, they are poorly suited for understanding the
eects of a medication with substantial heterogeneity in product characteristics and consumption methods across
the estimated 2.2 million state-legal medical cannabis patients in the United States25. Our observational study
using mobile app technology was designed to measure these eects in real-time among a large sample of patients
using cannabis for treating their medical symptoms under naturalistic conditions. On average, responders expe-
rienced signicant improvements across the 27 health symptom categories measured. Dried, whole natural ower
was associated with greater symptom relief than the use of other types of products (i.e., concentrates, edibles, tinc-
tures, and topicals). However, and despite the fact that dierent routes of administration deliver variable amounts
of cannabinoid contents and have dierent metabolomics2631, we did not nd variation in symptom relief with
use of pipes, joints, or vaporization combustion devices. Products made from pure C. indica strains were more
eective than products made from C. sativa, matching patient-reported preferences for the former for treating
conditions such as pain and insomnia32,33. However, once we controlled for cannabinoid contents, none of the
other product characteristics predicted variability in symptom levels. Only THC potency levels showed inde-
pendent associations with symptom relief and experiences of both positive and negative side eects, with higher
Figure 1. Adjusted Change in Symptom Severity by THC and CBD Percentage Category in Flower.
Figure 2. Adjusted Change in Symptom Severity by THC Percentage Category in Flower & Symptom Type.
Content courtesy of Springer Nature, terms of use apply. Rights reserved
6
SCIENTIFIC REPORTS | (2019) 9:2712 | https://doi.org/10.1038/s41598-019-39462-1
www.nature.com/scientificreports
www.nature.com/scientificreports/
levels resulting in larger eects. In contrast, we did not observe an independent link between CBD levels and any
of the omnibus symptom eects measured in the current study across nearly 20,000 user sessions.
Variability in cannabinoid proles may partially explain inconsistent ndings in the literature on, for exam-
ple, the benets of using cannabis for treating chronic neuropathic pain, with eectiveness observed in some
studies4,34, but not others35. Similarly, while many patient groups (e.g., sleep–disturbed medical cannabis users)
have reported a preference for high CBD concentrates36, we did not observe any patient outcomes varying by
CBD potency levels alone. One possibility is that many of the CBD potency levels displayed on labels of the
products consumed in the study were inaccurate (e.g., inated), as is currently common in the medical cannabis
industry37. Alternatively, it is possible that CBD has more latent eects than THC (e.g., expanding beyond the
90 minute observation window), has an impact on symptoms infrequently reported in our data, or that CBDs
eects may not lend themselves to perceptual detection and subjective reporting. e phytocannabinoid family
of CBDs are known to dier from other cannabinoids such as THC in several ways, including having no anity
to CB1 receptors, serving as an antagonist to GPR55 receptors and as an inverse modulator of the eects of THC
and perhaps the endocannabinoid system more generally, as well as functioning as an immuno-suppressant and
anti-inammatory agent38,39. us, it is possible that while CBD may operate inconspicuously to improve certain
health outcomes, the adjunctive consumption of THC is needed to consciously experience or be aware of such
eects.
Notwithstanding the innovative nature and potential implications of the study’s ndings, our observational,
quasi-eld experiment had unavoidable limitations, including the lack of a control group, e.g., non-cannabis
users with similar symptoms, salient characteristics, past experiences, and voluntary reporting, which could lead
to either: a) overestimation of the eectiveness of product characteristics if users who have negative experiences
with cannabis are more likely to drop out of the sample by choosing not to use the ReleafApp; or b) underestima-
tion of cannabis’ eectiveness if users fail to use the ReleafApp due to already being satised with their product
Variables
(1) (2) (3) (4) (5) (6)
Negative % of
Negative Positive % of Positive Context-
Specic % of Context-
Specic
Concentrate 0.024 0.008 0.097** 0.090** 0.052 0.001
(0.080) (0.028) (0.044) (0.037) (0.101) (0.062)
C. indica 0.079** 0.015*0.011 0.033** 0.030 0.045***
(0.035) (0.009) (0.017) (0.016) (0.026) (0.010)
C. sativa 0.003 0.002 0.000 0.022 0.041 0.043**
(0.045) (0.008) (0.012) (0.016) (0.033) (0.019)
Pipe 0.109 0.022 0.046 0.002 0.041 0.020
(0.077) (0.024) (0.060) (0.021) (0.045) (0.035)
Vap e 0.168** 0.037 0.044 0.004 0.050 0.047
(0.076) (0.024) (0.049) (0.024) (0.059) (0.031)
THC 10–14% 0.113*** 0.013 0.017 0.055*** 0.178*** 0.066***
(0.043) (0.010) (0.018) (0.015) (0.050) (0.020)
THC 15–34% 0.090*0.016 0.013 0.069*** 0.203*** 0.085***
(0.053) (0.013) (0.019) (0.018) (0.051) (0.021)
THC 35%+0.198** 0.050** 0.065*0.118*** 0.182** 0.095*
(0.091) (0.025) (0.036) (0.033) (0.072) (0.052)
CBD 1–9% 0.030 0.007 0.000 0.051*** 0.007 0.009
(0.042) (0.014) (0.015) (0.018) (0.038) (0.024)
CBD 10–34% 0.027 0.012 0.011 0.032*0.013 0.005
(0.029) (0.008) (0.013) (0.018) (0.047) (0.028)
CBD 35%+0.042 0.017 0.016 0.033 0.093 0.027
(0.062) (0.022) (0.024) (0.022) (0.070) (0.053)
Starting Symptom Level 0.005 0.003** 0.001 0.003 0.007 0.003
(0.007) (0.001) (0.002) (0.002) (0.005) (0.002)
Constant 0.566*** 0.108*** 0.988*** 0.288*** 0.629*** 0.160***
(0.081) (0.023) (0.048) (0.029) (0.077) (0.039)
Observations 3,220 3,220 3,220 3,220 3,220 3,220
R-squared 0.016 0.015 0.009 0.047 0.025 0.052
N Users 665 665 665 665 665 665
Table 3. Relative Associations of Product Characteristics with Side Eects. Notes: Regressions control for
individual user xed eects. e Concentrate is relative to Flower, C. indica and C. sativa are relative to Hybrid,
THC categories are relative to THC between 0 and 10%, and CBD categories are relative to 0% CBD, and Pipe
and Vape are relative to Joint. Standard errors are clustered at the user level (shown in parentheses). ***p < 0.01,
**p < 0.05, *p < 0.1.
Content courtesy of Springer Nature, terms of use apply. Rights reserved
7
SCIENTIFIC REPORTS | (2019) 9:2712 | https://doi.org/10.1038/s41598-019-39462-1
www.nature.com/scientificreports
www.nature.com/scientificreports/
choices and their eects. It is also important to note that the patient-reported outcomes were not cross-referenced
with clinical assessments. As with any observational study there is the potential confound of a placebo eect,
and given that cannabis products advertised as containing higher THC contents are generally more expensive
to consumers, they may be subject to a buyers justication eect (magnied appreciation to justify an added
expense of purchase). Another limitation is that the ReleafApp may be better suited to tracking the more imme-
diate responses of users of concentrates, ower, and to some extent, tinctures versus the longer to peak eects of
edibles and topicals. It is also possible that people who choose not to use the ReleafApp have dierent experiences
with product characteristics than those who do use the app. Another limitation was the inability to distinguish
subtleties across product types, such as pipes, which can vary in material construction and potential chemical
reactions (e.g., hydrolysis via water pipes). Finally, we anticipate that greater nuances exist in the eects of product
characteristics, and particularly, cannabinoid contents across symptom categories, but the current study is lim-
ited by our sample size within each respondent subgroup. Future research will capitalize on our ever increasing
sample size to analyze the pharmacodynamic interactions of major cannabinoids and other organic compounds
including terpenoids, as well as the harm of cannabis production practices. For example, the use of solvents to
extract cannabinoids for making concentrates used in making non-ower products (e.g., edibles, tinctures) may
place patients at risk for respiratory and cardiovascular problems40 and be a cause of increased emergency cases
of Cannabinoid Hyperemesis Syndrome41.
In conclusion, rapid increases in the popularity of medical cannabis and the associated increase in the number
of patients highlight the urgency of investigating and directing eective usage. Cannabis use carries the risk of
addiction and short-term impairments in cognitive and behavioral functioning, including the potential for safety
issues in the workplace or while driving. However, with preliminary evidence that cannabis may treat an even
wider range of conditions than those tracked in this study, including cancer42,43, it is imperative that the scientic
community develop innovative strategies such as the use of mobile technology for measuring the multidimen-
sional relationships among cannabis product characteristics, patient health conditions, perceived symptom relief,
and side eect manifestation.
Data Availability
e data that support the ndings of this study are available from MoreBetter Ltd. but restrictions apply to the
availability of these data, which were used under license for the current study, and so are not publicly available.
Data are however available from the authors upon reasonable request and with permission of MoreBetter Ltd.
References
1. Piper, B. J. et al. Substitution of medical cannabis for pharmaceutical agents for pain, anxiety, and sleep. J Psychopharmacol. 31,
569–575 (2017).
2. Hill, . P. & Weiss, . D. Minimal physical health ris associated with long-term cannabis use—but buyer beware. JAMA. 315,
2338–2339 (2016).
3. ubin, . Medical marijuana is legal in most states, but physicians have little evidence to guide them. JAMA. 317, 1611–1613 (2017).
4. National Academies of Sciences, Engineering, and Medicine; Health and Medicine Division; Board on Population Health and Public
Health Practice; Committee on the Health Eects of Marijuana: An Evidence eview and esearch Agenda. Washington (DC):
National Academies Press (US) (2017).
5. Stith, S. S. & Vigil, J. M. V. Federal barriers to Cannabis research. Science. 352, 1182 (2016).
6. Di Forti, M. et al. Proportion of patients in south London with rst-episode psychosis attributable to use of high potency cannabis:
A case-control study. e Lancet Psychiatry. 2, 233–238 (2015).
7. Gage, S. H. et al. Assessing causality in associations between cannabis use and schizophrenia ris: a two-sample Mendelian
randomization study. Psychological Medicine. 47, 971–980 (2017).
8. Fahoury, M. Could cannabidiol be used as an alternative to antipsychotics? Journal of Psychiatric Research. 80, 14–21 (2016).
9. Gururajan, A. & Malone, D. T. Does cannabidiol have a role in the treatment of schizophrenia? Schizophre nia Research. 176, 281–290
(206).
10. Iseger, T. A. & Bossong, M. G. A systematic review of the antipsychotic properties of cannabidiol in humans. Schizophrenia Research.
162, 153–161 (2015).
11. Christian, D. et al. Cannabis with high cannabidiol content is associated with fewer psychotic experiences. Schizophrenia Research.
130, 216–221 (2011).
12. National Institute of Drug Abuse. Marijuana as Medicine, https://www.drugabuse.gov/publications/drugfacts/marijuana-medicine
on (2018).
13. amo, D. E., Popova, L., Grana, ., Zhao, S. & Chavez, . Cannabis Mobile Apps: A Content Analysis. Eysenbach G, ed. JMIR
mHealth and uHealth. 3, e81 (2015).
14. eleafApp, https://releafapp.com/ (2018).
15. Vigil, J. M., Stith, S. S., Adams, I. M. & eeve, A. P. Associations between medical cannabis and prescription opioid use in chronic
pain patients: A preliminary cohort study. PLoS ONE. 12, e0187795 (2017).
16. indred, J. H. et al. Cannabis use in people with Parinsons disease and Multiple Sclerosis: A web-based investigation.
Complementary erapies in Medicine. 33, 99–104 (2017).
17. Bonn-Miller, M. O., Babson, . A. & Vandrey, . Using cannabis to help you sleep: Heightened frequency of medical cannabis use
among those with PTSD. Drug and Alcohol Dependence. 136, 162–165 (2014).
18. Costain, W. F. e eects of cannabis abuse on the symptoms of schizophrenia: Patient perspectives. International Journal of Mental
Health Nursing. 17, 227–235 (2008).
19. MacCallum, C. A. & usso, E. B. Practical considerations in medical cannabis administration and dosing. European Journal of
Internal Medicine. 49, 12–19 (2018).
20. Fischer, B. et al. Lower-ris cannabis use guidelines: A comprehensive update of evidence and recommendations. American Journal
of Public Health. 107, e1–e12 (2017).
21. Stith, S. S., Vigil, J. M., Brocelman, F., eenan, . & Hall, B. Patient-reported symptom relief following medical cannabis
consumption. Frontiers in Pharmacology. 9, 916, https://www.frontiersin.org/articles/10.3389/fphar.2018.00916/full (2018).
22. Vigil, J. M. et al. Eectiveness of raw, natural medical Cannabis ower for treating insomnia under naturalistic conditions. Medicines.
5, 75. https://www.mdpi.com/2305-6320/5/3/75 (2018).
23. Blundell, M., Dargan, P. & Wood, D. A cloud on the horizon-a survey into the use of electronic vaping devices for recreational drug
and new psychoactive substance (NPS) administration. QJM. 111, 9–14 (2018).
Content courtesy of Springer Nature, terms of use apply. Rights reserved
8
SCIENTIFIC REPORTS | (2019) 9:2712 | https://doi.org/10.1038/s41598-019-39462-1
www.nature.com/scientificreports
www.nature.com/scientificreports/
24. Eggers, M. E. et al. Youth use of electronic vapor products and blunts for administering cannabis. Addictive Behaviors. 70, 79–82
(2017).
25. Marijuana Policy Project, https://www.mpp.org/issues/medical-marijuana/state-by-state-medical-marijuana-laws/medical-
marijuana-patient-numbers/ (2018).
26. Dinis-Oliveira, . J. Metabolomics of Δ9-tetrahydrocannabinol: implications in toxicity. Drug Metabolism Reviews. 48, 80–87
(2016).
27. Lefever, T. W. et al. Vaping synthetic cannabinoids: A novel preclinical model of e-cigarette use in mice. Substance Abuse: Research
and Treatment. 11, https://doi.org/10.1177/1178221817701739 (2017).
28. Manwell, L. A. et al. A vapourized Δ9-tetrahydrocannabinol (Δ9-THC) delivery system part I: Development and validation of a
pulmonary cannabinoid route of exposure for experimental pharmacology studies in rodents. Journal of Pharmacological and
Toxicological Methods. 70, 120–127 (2014).
29. Nguyen, J. D. et al. Inhaled delivery of Δ9-tetrahydrocannabinol (THC) to rats by e-cigarette vapor technology. Neuropharmacology.
109, 112–120 (2016).
30. Vandrey, . et al. Pharmacoinetic profile of oral cannabis in humans: Blood and oral fluid disposition and relation to
pharmacodynamic outcomes. Journal of Analytical Toxicology. 41, 83–99 (2017).
31. Varlet, V. et al. Drug vaping applied to cannabis: Is “Cannavaping” a therapeutic alternative to marijuana? Scientic Reports. 6, 25599,
https://www.nature.com/articles/srep25599 (2016).
32. Cohen, N. L., Heinz, A. J., Ilgen, M. & Bonn-Miller, M. O. Pain, Cannabis Species, and Cannabis Use Disorders. Journal of Studies on
Alcohol and Drugs. 77, 515–520 (2016).
33. Pearce, D., Mitsouras, . & Irizarry, . Discriminating the Eects of Cannabis sativa and Cannabis indica: A Web Survey of Medical
Cannabis Users. Journal of Alternative & Complementary Medicine. 20, 787–791 (2014).
34. Andreae, M. H. et al. Inhaled cannabis for chronic neuropathic pain: an individual patient data meta-analysis. e Journal of Pain.
16, 1221–1232 (2015).
35. Müce, M., Phillips, T., adbruch, L., Petze, F. & Häuser, W. Cannabis-based medicines for chronic neuropathic pain in adults.
Cochrane Database of Systematic Reviews. 3, Art. No.: CD012182. https://doi.org/10.1002/14651858.CD012182.pub2 (2018).
36. Belendiu, . A., Babson, . A., Vandrey, . & Bonn-Miller, M. O. Cannabis species and cannabinoid concentration preference
among sleep-disturbed medicinal cannabis users. Addictive Behaviors. 50, 178–181 (2015).
37. Bonn-Miller, M. O. et al. Labeling accuracy of cannabidiol extracts sold online. JAMA. 318, 1708–1709 (2017).
38. Burstein, S. Cannabidiol (CBD) and its analogs: a review of their eects on inammation. Bioorganic & Medicinal Chemistry. 23,
1377–1385 (2017).
39. McPartland, J. M., Duncan, M., Di Marzo, V. & Pertwee, . G. Are cannabidiol and Δ9-tetrahydrocannabivarin negative modulators
of the endocannabinoid system? A systematic review. British Journal of Pharmacology. 172, 737–753 (2015).
40. Piano, M. Cannabis smoing and cardiovascular health: It’s complicated. Clin. Pharmacol. er. 102, 191–193 (2017).
41. ichards, J. . Cannabinoid hyperemesis syndrome: Pathophysiology and treatment in the emergency department. Journal of
Emergency Medicine. 54, 354–363 (2018).
42. Fowler, C. Delta9-tetrahydrocannabinol and cannabidiol as potential curative agents for cancer: A critical examination of the
preclinical literature. Clin. Pharmacol. er. 97, 587–596 (2015).
43. Śledzińsi, P., Zeyland, J., Słomsi, . & Nowa, A. e current state and future perspectives of cannabinoids in cancer biology.
Cancer Medicine. 7, 765–775 (2018).
Acknowledgements
is research was funded in part by donations to the University of New Mexico Medical Cannabis Research Fund
(mcrf.unm.edu). All authors had access to the data in the study and take responsibility for the integrity of the data
and the accuracy of the data analyses.
Author Contributions
J.M.V. and S.S.S. conceived the study. F.B., K.K., B.H. independently designed and developed the ReleafApp and
server infrastructure as part of their eort to help create an education tool for medical cannabis patients. S.S.S.
conducted the analyses. J.M.V. and S.S.S. draed the manuscript. All authors contributed substantially to its
intellectual content and revision.
Additional Information
Supplementary information accompanies this paper at https://doi.org/10.1038/s41598-019-39462-1.
Competing Interests: e authors are associated with the University of New Mexico Medical Cannabis
Research Fund, which was designed to support the costs of research investigating the safety and eectiveness of
medical cannabis. F.B., K.K. and B.H. are employed by MoreBetter Ltd. e authors have no other conicts of
interest.
Publisher’s note: Springer Nature remains neutral with regard to jurisdictional claims in published maps and
institutional aliations.
Open Access This article is licensed under a Creative Commons Attribution 4.0 International
License, which permits use, sharing, adaptation, distribution and reproduction in any medium or
format, as long as you give appropriate credit to the original author(s) and the source, provide a link to the Cre-
ative Commons license, and indicate if changes were made. e images or other third party material in this
article are included in the article’s Creative Commons license, unless indicated otherwise in a credit line to the
material. If material is not included in the article’s Creative Commons license and your intended use is not per-
mitted by statutory regulation or exceeds the permitted use, you will need to obtain permission directly from the
copyright holder. To view a copy of this license, visit http://creativecommons.org/licenses/by/4.0/.
© e Author(s) 2019
Content courtesy of Springer Nature, terms of use apply. Rights reserved
1.
2.
3.
4.
5.
6.
Terms and Conditions
Springer Nature journal content, brought to you courtesy of Springer Nature Customer Service Center GmbH (“Springer Nature”).
Springer Nature supports a reasonable amount of sharing of research papers by authors, subscribers and authorised users (“Users”), for small-
scale personal, non-commercial use provided that all copyright, trade and service marks and other proprietary notices are maintained. By
accessing, sharing, receiving or otherwise using the Springer Nature journal content you agree to these terms of use (“Terms”). For these
purposes, Springer Nature considers academic use (by researchers and students) to be non-commercial.
These Terms are supplementary and will apply in addition to any applicable website terms and conditions, a relevant site licence or a personal
subscription. These Terms will prevail over any conflict or ambiguity with regards to the relevant terms, a site licence or a personal subscription
(to the extent of the conflict or ambiguity only). For Creative Commons-licensed articles, the terms of the Creative Commons license used will
apply.
We collect and use personal data to provide access to the Springer Nature journal content. We may also use these personal data internally within
ResearchGate and Springer Nature and as agreed share it, in an anonymised way, for purposes of tracking, analysis and reporting. We will not
otherwise disclose your personal data outside the ResearchGate or the Springer Nature group of companies unless we have your permission as
detailed in the Privacy Policy.
While Users may use the Springer Nature journal content for small scale, personal non-commercial use, it is important to note that Users may
not:
use such content for the purpose of providing other users with access on a regular or large scale basis or as a means to circumvent access
control;
use such content where to do so would be considered a criminal or statutory offence in any jurisdiction, or gives rise to civil liability, or is
otherwise unlawful;
falsely or misleadingly imply or suggest endorsement, approval , sponsorship, or association unless explicitly agreed to by Springer Nature in
writing;
use bots or other automated methods to access the content or redirect messages
override any security feature or exclusionary protocol; or
share the content in order to create substitute for Springer Nature products or services or a systematic database of Springer Nature journal
content.
In line with the restriction against commercial use, Springer Nature does not permit the creation of a product or service that creates revenue,
royalties, rent or income from our content or its inclusion as part of a paid for service or for other commercial gain. Springer Nature journal
content cannot be used for inter-library loans and librarians may not upload Springer Nature journal content on a large scale into their, or any
other, institutional repository.
These terms of use are reviewed regularly and may be amended at any time. Springer Nature is not obligated to publish any information or
content on this website and may remove it or features or functionality at our sole discretion, at any time with or without notice. Springer Nature
may revoke this licence to you at any time and remove access to any copies of the Springer Nature journal content which have been saved.
To the fullest extent permitted by law, Springer Nature makes no warranties, representations or guarantees to Users, either express or implied
with respect to the Springer nature journal content and all parties disclaim and waive any implied warranties or warranties imposed by law,
including merchantability or fitness for any particular purpose.
Please note that these rights do not automatically extend to content, data or other material published by Springer Nature that may be licensed
from third parties.
If you would like to use or distribute our Springer Nature journal content to a wider audience or on a regular basis or in any other manner not
expressly permitted by these Terms, please contact Springer Nature at
onlineservice@springernature.com

Supplementary resource (1)

... THC is the major psychoactive substance reported to affect mood, orientation, appetite and pain perception. CBD is not psychoactive, but is reported to have analgesic, anxiolytic and anti-inflammatory effects [36]. At the receptor level, for CB1, THC is a partial agonist whilst CBD is a negative allosteric modulator [36]. ...
... CBD is not psychoactive, but is reported to have analgesic, anxiolytic and anti-inflammatory effects [36]. At the receptor level, for CB1, THC is a partial agonist whilst CBD is a negative allosteric modulator [36]. ...
Article
Full-text available
Fibromyalgia is a chronic health condition characterized by chronic pain fatigue, sleep disturbances and many other symptoms affecting a patient’s quality of life. Patients with fibromyalgia often visit rheumatology outpatients with a long list of symptoms and often receive multiple medications. Many have seen multiple specialists and have done a lot of reading about alternative modalities of treatment. The limited effectiveness of conventional therapy coupled with widespread media attention raises the question of cannabis use. This review examines the literature on cannabinoid use in fibromyalgia against the context of the international variation in legal frameworks, the available products and the outcomes reported. A detailed review was performed using the EMBASE and PUBMED databases. It was concluded that despite the interest in the use of cannabinoids in the management of fibromyalgia, there is insufficient evidence to prescribe the currently available licensed medicines or to recommend the complementary health products available for legal purchase. There is a need for more global clinical randomised trials to accurately determine medicinal cannabis short and long-term long efficacy and safety for its acute and chronic use.
... Cannabis-derived products have complex pharmacological characteristics, such as the opposing pharmacological and behavioral effects of the two main constituents of cannabis (Morgan et al., 2010), further complicated by the high variability of cannabis products in terms of their pharmacodynamics and kinetics features, as well as their delivery through various routes of administration. In addition to the approved indications for which there is scientific evidence, there is a hype about the use of many cannabis-derived products for a variety of conditions (Eisenstein, 2019;Stith et al., 2019), with the market of CBD in the wellness industry in the United States of America (US) predicted to be at US$24 billion by 2023 (Giammona & Einhorn, 2019). The previous history of cannabis as a recreational drug could also potentially lead to a polarized view on its medical use, with either uncritical support independent of scientific evidence or a negative bias. ...
Article
Full-text available
Background There is a growing literature on the potential medical uses of Cannabis sativa and cannabinoid compounds. Although these have only been approved by regulatory agencies for a few indications, there is a hype about their possible benefits in a variety of conditions and a large market in the wellness industry. As in many cases patients search for information on cannabis products online, we have analyzed the information on medical cannabis available on the Internet. Therefore, this study aims at assessing the quality of the information available online on medical cannabis. Methods We searched “medical cannabis” on June 2019 using google.com and downloaded the first 243 websites. After excluding dead links or websites with no information about cannabis, 176 websites were included. They were then classified for their typology (e.g., commercial, government, news outlets). As an indicator of trustworthiness, we used the Journal of American Medical Association (JAMA) score, which assesses the indication of date, author, ownership of the website, and the presence of references. We also considered if a website is certified by Health-On-the-Net (HON), an independent organization, by displaying a HONCode symbol. Subsequently, we performed a content analysis to assess both the medical cannabis indications mentioned by webpages and the completeness of the information provided (whether they mentioned potential side effects and legal/regulatory issues or not). Results Analyzing 176 webpages returned by a search engine, we found that 52% of them were news websites. Pain, epilepsy, and multiple sclerosis were the most frequently mentioned therapeutic areas (cited in 92, 84 and 80 webpages, respectively), which did not always match those for which there is regulatory approval. Information was also incomplete, with only 22% of the webpages mentioning potential side effects. Health portal websites provided the most complete information, with all of them ( n = 7) reporting side effects. On average, 80% of webpages had a neutral stance on the potential benefits of medical cannabis, with commercial websites having more frequently a positive stance (67%). Conclusions We conclude that the information that can be found online is not always aligned in terms of the therapeutic areas for which science-based evidence is often still weak.
... Although the causal relation between cannabis use and its side-effects is not clear now, frequent use of cannabis-based products is associated with some short-and long-term effects like respiratory and cardiovascular disorders, cognitive alterations, psychosis, schizophrenia, and mood disorders [6]. However, Stith et al.'s [7] study shows that CBD, in particular, did not necessarily improve any health issues but neither caused side effects based on self-reporting. But FDA's guidelines indicate that the scientific community still does not know what happens if CBD is used daily for prolonged periods of time, in terms of its safety profile. ...
Conference Paper
Full-text available
Although the U.S. FDA has only approved exactly one cannabidiol (CBD) drug product (specifically to treat seizures), CBD products are proliferating rapidly through different modes of usage including food products, cosmetics, vaping pods, and supplements (typically, oils). Despite the FDA clearly warning consumers about unproven health claims made by manufacturers selling CBD products over the counter, the CBD market share was nearly 3 billion USD in 2020 and is expected to top 55 billion USD in 2028. In this context, it is important to assess the presence of health claims being made on social media, especially claims that are part of marketing messages. To this end, we collected over two million English tweets discussing CBD themes. We created a hand-labeled dataset and built machine learned classifiers to identify marketing tweets from regular tweets that may be generated by consumers. The best classifier achieved 85% precision, 83% recall, and 84% F-score. Our analyses showed that pain, anxiety disorders, sleep disorders, and stress are the four main therapeutic claims made constituting 31.67%, 27.11%, 13.77%, and 10.37% of all medical claims made on Twitter, respectively. Also, more than 93% of advertised CBD products are edibles or oil/tinctures. Our effort is the first to demonstrate the feasibility of surveillance of marketing claims for CBD products. We believe this could pave way for more explorations into this indispensable task in the current landscape of social media driven health (mis)information and communication.
... Given this, it remains unclear whether the perceived therapeutic effects are a result of the individual components of cannabis products or the combined effects of interacting cannabinoids and terpenes. Although strain categories are largely arbitrary, many researchers continue to examine their perceived effects to better understand consumer choices [16,24,[44][45][46][47]. The nature of our data allowed us to do the same, providing insight into the naturalistic setting of cannabis use. ...
Preprint
BACKGROUND Insomnia is a prevalent condition that presents itself at both the symptom and diagnostic levels. Although insomnia is one of the main reasons individuals seek medicinal cannabis, little is known about the profile of cannabinoid use or the perceived benefit of the use of cannabinoids in daily life. OBJECTIVE We conducted a retrospective study of medicinal cannabis users to investigate the use profile and perceived efficacy of cannabinoids for the management of insomnia. METHODS Data were collected using the Strainprint app, which allows medicinal cannabis users to log conditions and symptoms, track cannabis use, and monitor symptom severity pre- and postcannabis use. Our analyses examined 991 medicinal cannabis users with insomnia across 24,189 tracked cannabis use sessions. Sessions were analyzed, and both descriptive statistics and linear mixed-effects modeling were completed to examine use patterns and perceived efficacy. RESULTS Overall, cannabinoids were perceived to be efficacious across all genders and ages, and no significant differences were found among product forms, ingestion methods, or gender groups. Although all strain categories were perceived as efficacious, predominant indica strains were found to reduce insomnia symptomology more than cannabidiol (CBD) strains (estimated mean difference 0.59, SE 0.11; 95% CI 0.36-0.81; adjusted P <.001) and predominant sativa strains (estimated mean difference 0.74, SE 0.16; 95% CI 0.43-1.06; adjusted P <.001). Indica hybrid strains also presented a greater reduction in insomnia symptomology than CBD strains (mean difference 0.52, SE 0.12; 95% CI 0.29-0.74; adjusted P <.001) and predominant sativa strains (mean difference 0.67, SE 0.16; 95% CI 0.34-1.00; adjusted P =.002). CONCLUSIONS Medicinal cannabis users perceive a significant improvement in insomnia with cannabinoid use, and this study suggests a possible advantage with the use of predominant indica strains compared with predominant sativa strains and exclusively CBD in this population. This study emphasizes the need for randomized placebo-controlled trials assessing the efficacy and safety profile of cannabinoids for the treatment of insomnia.
... Given this, it remains unclear whether the perceived therapeutic effects are a result of the individual components of cannabis products or the combined effects of interacting cannabinoids and terpenes. Although strain categories are largely arbitrary, many researchers continue to examine their perceived effects to better understand consumer choices [16,24,[44][45][46][47]. The nature of our data allowed us to do the same, providing insight into the naturalistic setting of cannabis use. ...
Article
Background Insomnia is a prevalent condition that presents itself at both the symptom and diagnostic levels. Although insomnia is one of the main reasons individuals seek medicinal cannabis, little is known about the profile of cannabinoid use or the perceived benefit of the use of cannabinoids in daily life. Objective We conducted a retrospective study of medicinal cannabis users to investigate the use profile and perceived efficacy of cannabinoids for the management of insomnia. Methods Data were collected using the Strainprint app, which allows medicinal cannabis users to log conditions and symptoms, track cannabis use, and monitor symptom severity pre- and postcannabis use. Our analyses examined 991 medicinal cannabis users with insomnia across 24,189 tracked cannabis use sessions. Sessions were analyzed, and both descriptive statistics and linear mixed-effects modeling were completed to examine use patterns and perceived efficacy. Results Overall, cannabinoids were perceived to be efficacious across all genders and ages, and no significant differences were found among product forms, ingestion methods, or gender groups. Although all strain categories were perceived as efficacious, predominant indica strains were found to reduce insomnia symptomology more than cannabidiol (CBD) strains (estimated mean difference 0.59, SE 0.11; 95% CI 0.36-0.81; adjusted P<.001) and predominant sativa strains (estimated mean difference 0.74, SE 0.16; 95% CI 0.43-1.06; adjusted P<.001). Indica hybrid strains also presented a greater reduction in insomnia symptomology than CBD strains (mean difference 0.52, SE 0.12; 95% CI 0.29-0.74; adjusted P<.001) and predominant sativa strains (mean difference 0.67, SE 0.16; 95% CI 0.34-1.00; adjusted P=.002). Conclusions Medicinal cannabis users perceive a significant improvement in insomnia with cannabinoid use, and this study suggests a possible advantage with the use of predominant indica strains compared with predominant sativa strains and exclusively CBD in this population. This study emphasizes the need for randomized placebo-controlled trials assessing the efficacy and safety profile of cannabinoids for the treatment of insomnia.
... The study lacks data on pain and other symptom levels immediately prior to MC use. Observational studies of MC use in naturalistic settings, capturing pain levels immediately prior to, and within hours after MC administration have found evidence of pain relief (30,37,38). The study also lacks data on symptoms of CUD. ...
Article
Full-text available
Background: Little research has tested associations of pain and MC use after long-term treatment and through methods that have external validity outside experimental settings. The study examined associations of pain, associated painful experiences, and long-term medical cannabis (MC) use in chronic pain (CP) patients using a naturalistic daily diary study that provided novel and externally valid data. Methods: Data were obtained from 78 MC users with CP three times daily over a 10-day period (n observations = 1,688). Mixed-effects models were used to test the associations between MC use and momentary experiences of pain, affect, and fatigue. Results: Within persons, elevated experiences of pain intensity were associated with greater intention to use MC within the next hour. No evidence was found that the time lapse since last MC use was associated with pain levels, negative affect, or fatigue. Conclusions: The results imply that after long-term use, CP patients intend to use MC in response to pain experiences. Yet, they may not actually achieve the pain relief. More research is needed to examine whether continued MC use despite lack of pain relief is related to relief of other symptoms (e.g., dependence, withdrawal) or positive benefits (e.g., general sense of well-being) or tolerance.
Article
Recreational marijuana legislation (RML) has been enacted at the state-level but not federally. Given the link between public opinion and RML, we examine 2021 national poll ( N = 995) data that assessed views about different types of proposed federal actions concerning cannabis. Less than half of Americans preferred full legalization, 21% approved of medical legalization only, 23% believed in states’ rights, and 11% supported the current prohibition. Using multinomial logistic regression modeling, respondents who associated legalized recreational marijuana with adverse/negative effects were less likely to favor full legalization. In contrast, respondents who associated legalized recreational marijuana with beneficial effects were most supportive of full legalization. Uncertainty surrounding cannabis shaped preferences but not as dramatically as having a clear opinion.
Article
Session 2 of the National Cancer Institute’s Cannabis, Cannabinoids, and Cancer Research Workshop opened with testimony from a lymphoma survivor who detailed medicinal cannabis-related improvements in nausea, low appetite, insomnia, and mental health and the limited clinical counsel she received regarding cannabis use. Discussion next turned to the evolution of the legal landscape of cannabis in the United States, one in which state and federal laws frequently conflict and the Controlled Substance Act renders cannabis Schedule I. This legal climate creates conundrums for US medicinal cannabis researchers who contend with limited funding opportunities, avenues to source trial drug, and procedural red tape and for oncology clinicians who recommend medicinal cannabis to patients with some frequency while perceiving themselves as ill equipped to make such clinical recommendations. Ultimately, it creates challenges for cancer patients who find themselves turning to nonmedical and anecdotal information sources. The risks of cannabis use by the cancer patient were discussed next. These include infection, pharmacodynamic and pharmacokinetic drug-botanical interactions, cyclic nausea and vomiting, e-cigarette or vaping product use–associated illness, legal issues, and high cost. The session concluded with a broad survey of the research supporting oncologic cannabinoid use, conclusive evidence for chemotherapy-induced nausea and vomiting, and suggestive evidence for cancer-related pain.
Article
Full-text available
Recreational cannabis markets possibly increase labor demand through investments in facilities for growing, processing, and retail sales of cannabis, as well as through other industries such as manufacturing, leisure, and hospitality. However, this increase in labor demand may vary substantially across counties within a state as most states with legal recreational cannabis allow individual counties to ban commercial cannabis sales. Meanwhile, labor supply may change through positive and negative effects from cannabis use. Using county-level Colorado data from 2011 to 2018 and exploiting variation across counties in the existence and timing of the start of dispensary sales, we test for changes in the unemployment rate, employment, and wages, overall and by industry subsector. Consistent with an increase in labor demand, we estimate that the sale of recreational cannabis through dispensaries is associated with a 0.7 percentage point decrease in the unemployment rate with no effect on the size of the labor force. We also find a 4.5% increase in the number of employees, with the strongest effects found in manufacturing. We find no effect on wages. Given the lack of a reduction in labor force participation or wages, negative effects on labor supply are likely limited, in line with the existing literature. The decrease in unemployment, coupled with an increase in the number of employees, indicates that labor demand effects likely dominate effects on labor supply. Our results suggest that policymakers considering recreational access to cannabis should anticipate a possible increase in employment.
Article
Background Cannabis can have an adverse impact on some mental health conditions, while many consumers report using cannabis to manage or improve mental health. Little data exists on how patterns of cannabis use differ by mental health status. The current study examined the prevalence of cannabis use and modes of cannabis administration among consumers who experienced a mental health condition in the past 12-months. Methods Data came from the International Cannabis Policy Study (Wave 1). Online surveys were conducted in Aug – Oct 2018 with 25,747 respondents aged 16-65, recruited from commercial panels in Canada and the US. Multinomial and binary regression models examined differences in cannabis prevalence and use of nine cannabis product types among those with and without self-reported past 12-month experience of anxiety, depression, PTSD, bipolar disorder, and psychosis. Results Respondents with each of the five mental health conditions reported more frequent cannabis use than those without a mental health condition (p<.01). Past 12-month cannabis consumers who experienced mental health conditions were significantly more likely to use the most potent products (solid concentrates, THC vape oils, hash) (p<.05), with fewer differences for dried flower, edibles, and other forms. Patterns of use were similar across specific mental health conditions, with some differences among respondents reporting psychosis and bipolar disorder. Conclusion Individuals experiencing mental health conditions report more frequent cannabis use and use of more potent product types. These findings highlight the need to target use of specific high potency products in prevention, treatment, and harm reduction among these populations.
Article
Full-text available
Background: The Releaf AppTM mobile software application (app) data was used to measure self-reported effectiveness and side effects of medical cannabis used under naturalistic conditions. Methods: Between 5/03/2016 and 12/16/2017, 2,830 Releaf AppTM users completed 13,638 individual sessions self-administering medical cannabis and indicated their primary health symptom severity rating on an 11-point (0–10) visual analog scale in real-time prior to and following cannabis consumption, along with experienced side effects. Results: Releaf AppTM responders used cannabis to treat myriad health symptoms, the most frequent relating to pain, anxiety, and depressive conditions. Significant symptom severity reductions were reported for all the symptom categories, with mean reductions between 2.8 and 4.6 points (ds ranged from 1.29–2.39, ps < 0.001). On average, higher pre-dosing symptom levels were associated with greater reported symptom relief, and users treating anxiety or depression-related symptoms reported significantly more relief (ps < 0.001) than users with pain symptoms. Of the 42 possible side effects, users were more likely to indicate and showed a stronger correlation between symptom relief and experiences of positive (94% of sessions) or a context-specific side effects (76%), whereas negative side effects (60%) were associated with lessened, yet still significant symptom relief and were more common among patients treating a depressive symptom relative to patients treating anxiety and pain-related conditions. Conclusion: Patient-managed cannabis use is associated with clinically significant improvements in self-reported symptom relief for treating a wide range of health conditions, along with frequent positive and negative side effects.
Article
Full-text available
Background: We use a mobile software application (app) to measure for the first time, which fundamental characteristics of raw, natural medical Cannabis flower are associated with changes in perceived insomnia under naturalistic conditions. Methods: Four hundred and nine people with a specified condition of insomnia completed 1056 medical cannabis administration sessions using the Releaf AppTM educational software during which they recorded real-time ratings of self-perceived insomnia severity levels prior to and following consumption, experienced side effects, and product characteristics, including combustion method, cannabis subtypes, and/or major cannabinoid contents of cannabis consumed. Within-user effects of different flower characteristics were modeled using a fixed effects panel regression approach with standard errors clustered at the user level. Results: Releaf AppTM users showed an average symptom severity reduction of −4.5 points on a 0–10 point visual analogue scale (SD = 2.7, d = 2.10, p < 0.001). Use of pipes and vaporizers was associated with greater symptom relief and more positive and context-specific side effects as compared to the use of joints, while vaporization was also associated with lower negative effects. Cannabidiol (CBD) was associated with greater statistically significant symptom relief than tetrahydrocannabinol (THC), but the cannabinoid levels generally were not associated with differential side effects. Flower from C. sativa plants was associated with more negative side effects than flower from C. indica or hybrid plant subtypes. Conclusions: Consumption of medical Cannabis flower is associated with significant improvements in perceived insomnia with differential effectiveness and side effect profiles, depending on the product characteristics.
Article
Full-text available
BACKGROUND: This review is one of a series on drugs used to treat chronic neuropathic pain. Estimates of the population prevalence of chronic pain with neuropathic components range between 6% and 10%. Current pharmacological treatment options for neuropathic pain afford substantial benefit for only a few people, often with adverse effects that outweigh the benefits. There is a need to explore other treatment options, with different mechanisms of action for treatment of conditions with chronic neuropathic pain. Cannabis has been used for millennia to reduce pain. Herbal cannabis is currently strongly promoted by some patients and their advocates to treat any type of chronic pain. OBJECTIVES: To assess the efficacy, tolerability, and safety of cannabis-based medicines (herbal, plant-derived, synthetic) compared to placebo or conventional drugs for conditions with chronic neuropathic pain in adults. SEARCH METHODS: In November 2017 we searched CENTRAL, MEDLINE, Embase, and two trials registries for published and ongoing trials, and examined the reference lists of reviewed articles. SELECTION CRITERIA: We selected randomised, double-blind controlled trials of medical cannabis, plant-derived and synthetic cannabis-based medicines against placebo or any other active treatment of conditions with chronic neuropathic pain in adults, with a treatment duration of at least two weeks and at least 10 participants per treatment arm. DATA COLLECTION AND ANALYSIS: Three review authors independently extracted data of study characteristics and outcomes of efficacy, tolerability and safety, examined issues of study quality, and assessed risk of bias. We resolved discrepancies by discussion. For efficacy, we calculated the number needed to treat for an additional beneficial outcome (NNTB) for pain relief of 30% and 50% or greater, patient's global impression to be much or very much improved, dropout rates due to lack of efficacy, and the standardised mean differences for pain intensity, sleep problems, health-related quality of life (HRQoL), and psychological distress. For tolerability, we calculated number needed to treat for an additional harmful outcome (NNTH) for withdrawal due to adverse events and specific adverse events, nervous system disorders and psychiatric disorders. For safety, we calculated NNTH for serious adverse events. Meta-analysis was undertaken using a random-effects model. We assessed the quality of evidence using GRADE and created a 'Summary of findings' table. MAIN RESULTS: We included 16 studies with 1750 participants. The studies were 2 to 26 weeks long and compared an oromucosal spray with a plant-derived combination of tetrahydrocannabinol (THC) and cannabidiol (CBD) (10 studies), a synthetic cannabinoid mimicking THC (nabilone) (two studies), inhaled herbal cannabis (two studies) and plant-derived THC (dronabinol) (two studies) against placebo (15 studies) and an analgesic (dihydrocodeine) (one study). We used the Cochrane 'Risk of bias' tool to assess study quality. We defined studies with zero to two unclear or high risks of bias judgements to be high-quality studies, with three to five unclear or high risks of bias to be moderate-quality studies, and with six to eight unclear or high risks of bias to be low-quality studies. Study quality was low in two studies, moderate in 12 studies and high in two studies. Nine studies were at high risk of bias for study size. We rated the quality of the evidence according to GRADE as very low to moderate.Primary outcomesCannabis-based medicines may increase the number of people achieving 50% or greater pain relief compared with placebo (21% versus 17%; risk difference (RD) 0.05 (95% confidence interval (CI) 0.00 to 0.09); NNTB 20 (95% CI 11 to 100); 1001 participants, eight studies, low-quality evidence). We rated the evidence for improvement in Patient Global Impression of Change (PGIC) with cannabis to be of very low quality (26% versus 21%;RD 0.09 (95% CI 0.01 to 0.17); NNTB 11 (95% CI 6 to 100); 1092 participants, six studies). More participants withdrew from the studies due to adverse events with cannabis-based medicines (10% of participants) than with placebo (5% of participants) (RD 0.04 (95% CI 0.02 to 0.07); NNTH 25 (95% CI 16 to 50); 1848 participants, 13 studies, moderate-quality evidence). We did not have enough evidence to determine if cannabis-based medicines increase the frequency of serious adverse events compared with placebo (RD 0.01 (95% CI -0.01 to 0.03); 1876 participants, 13 studies, low-quality evidence).Secondary outcomesCannabis-based medicines probably increase the number of people achieving pain relief of 30% or greater compared with placebo (39% versus 33%; RD 0.09 (95% CI 0.03 to 0.15); NNTB 11 (95% CI 7 to 33); 1586 participants, 10 studies, moderate quality evidence). Cannabis-based medicines may increase nervous system adverse events compared with placebo (61% versus 29%; RD 0.38 (95% CI 0.18 to 0.58); NNTH 3 (95% CI 2 to 6); 1304 participants, nine studies, low-quality evidence). Psychiatric disorders occurred in 17% of participants using cannabis-based medicines and in 5% using placebo (RD 0.10 (95% CI 0.06 to 0.15); NNTH 10 (95% CI 7 to 16); 1314 participants, nine studies, low-quality evidence).We found no information about long-term risks in the studies analysed.Subgroup analysesWe are uncertain whether herbal cannabis reduces mean pain intensity (very low-quality evidence). Herbal cannabis and placebo did not differ in tolerability (very low-quality evidence). AUTHORS' CONCLUSIONS: The potential benefits of cannabis-based medicine (herbal cannabis, plant-derived or synthetic THC, THC/CBD oromucosal spray) in chronic neuropathic pain might be outweighed by their potential harms. The quality of evidence for pain relief outcomes reflects the exclusion of participants with a history of substance abuse and other significant comorbidities from the studies, together with their small sample sizes.
Article
Full-text available
To date, cannabinoids have been allowed in the palliative medicine due to their analgesic and antiemetic effects, but increasing number of preclinical studies indicates their anticancer properties. Cannabinoids exhibit their action by a modulation of the signaling pathways crucial in the control of cell proliferation and survival. Many in vitro and in vivo experiments have shown that cannabinoids inhibit proliferation of cancer cells, stimulate autophagy and apoptosis, and have also a potential to inhibit angiogenesis and metastasis. In this review, we present an actual state of knowledge regarding molecular mechanisms of cannabinoids’ anticancer action, but we discuss also aspects that are still not fully understood such as the role of the endocannabinoid system in a carcinogenesis, the impact of cannabinoids on the immune system in the context of cancer development, or the cases of a stimulation of cancer cells’ proliferation by cannabinoids. The review includes also a summary of currently ongoing clinical trials evaluating the safety and efficacy of cannabinoids as anticancer agents.
Article
Full-text available
Cannabis has been employed medicinally throughout history, but its recent legal prohibition, biochemical complexity and variability, quality control issues, previous dearth of appropriately powered randomised controlled trials, and lack of pertinent education have conspired to leave clinicians in the dark as to how to advise patients pursuing such treatment. With the advent of pharmaceutical cannabis-based medicines (Sativex/nabiximols and Epidiolex), and liberalisation of access in certain nations, this ignorance of cannabis pharmacology and therapeutics has become untenable. In this article, the authors endeavour to present concise data on cannabis pharmacology related to tetrahydrocannabinol (THC), cannabidiol (CBD) et al., methods of administration (smoking, vaporisation, oral), and dosing recommendations. Adverse events of cannabis medicine pertain primarily to THC, whose total daily dose-equivalent should generally be limited to 30mg/day or less, preferably in conjunction with CBD, to avoid psychoactive sequelae and development of tolerance. CBD, in contrast to THC, is less potent, and may require much higher doses for its adjunctive benefits on pain, inflammation, and attenuation of THC-associated anxiety and tachycardia. Dose initiation should commence at modest levels, and titration of any cannabis preparation should be undertaken slowly over a period of as much as two weeks. Suggestions are offered on cannabis-drug interactions, patient monitoring, and standards of care, while special cases for cannabis therapeutics are addressed: epilepsy, cancer palliation and primary treatment, chronic pain, use in the elderly, Parkinson disease, paediatrics, with concomitant opioids, and in relation to driving and hazardous activities.
Article
Full-text available
Background: Current levels and dangers of opioid use in the U.S. warrant the investigation of harm-reducing treatment alternatives. Purpose: A preliminary, historical, cohort study was used to examine the association between enrollment in the New Mexico Medical Cannabis Program (MCP) and opioid prescription use. Methods: Thirty-seven habitual opioid using, chronic pain patients (mean age = 54 years; 54% male; 86% chronic back pain) enrolled in the MCP between 4/1/2010 and 10/3/2015 were compared to 29 non-enrolled patients (mean age = 60 years; 69% male; 100% chronic back pain). We used Prescription Monitoring Program opioid records over a 21 month period (first three months prior to enrollment for the MCP patients) to measure cessation (defined as the absence of opioid prescriptions activity during the last three months of observation) and reduction (calculated in average daily intravenous [IV] morphine dosages). MCP patient-reported benefits and side effects of using cannabis one year after enrollment were also collected. Results: By the end of the 21 month observation period, MCP enrollment was associated with 17.27 higher age- and gender-adjusted odds of ceasing opioid prescriptions (CI 1.89 to 157.36, p = 0.012), 5.12 higher odds of reducing daily prescription opioid dosages (CI 1.56 to 16.88, p = 0.007), and a 47 percentage point reduction in daily opioid dosages relative to a mean change of positive 10.4 percentage points in the comparison group (CI -90.68 to -3.59, p = 0.034). The monthly trend in opioid prescriptions over time was negative among MCP patients (-0.64mg IV morphine, CI -1.10 to -0.18, p = 0.008), but not statistically different from zero in the comparison group (0.18mg IV morphine, CI -0.02 to 0.39, p = 0.081). Survey responses indicated improvements in pain reduction, quality of life, social life, activity levels, and concentration, and few side effects from using cannabis one year after enrollment in the MCP (ps<0.001). Conclusions: The clinically and statistically significant evidence of an association between MCP enrollment and opioid prescription cessation and reductions and improved quality of life warrants further investigations on cannabis as a potential alternative to prescription opioids for treating chronic pain.
Article
Full-text available
There is growing consumer demand for cannabidiol (CBD), a constituent of the cannabis plant, due to its purported medicinal benefits for myriad health conditions.¹ Viscous plant-derived extracts, suspended in oil, alcohol (tincture), or vaporization liquid, represent most of the retail market for CBD. Discrepancies between federal and state cannabis laws have resulted in inadequate regulation and oversight, leading to inaccurate labeling of some products.² To maximize sampling and ensure representativeness of available products, we examined the label accuracy of CBD products sold online, including identification of present but unlabeled cannabinoids.
Article
Background: Cannabinoid hyperemesis syndrome (CHS) is a challenging clinical disorder. CHS patients frequently present to the emergency department and may require treatment for intractable emesis, dehydration, and electrolyte abnormalities. Thought to be a variant of cyclic vomiting syndrome, CHS has become more prevalent with increasing cannabis potency and use, as enabled by various states having legalized the recreational use of cannabis. Objective: This aim of this review is to investigate the pathophysiology of CHS and evaluate the published literature on pharmacologic treatment in the emergency department. This information may be helpful in providing evidence-based, efficacious antiemetic treatment grounded in knowledge of antiemetic medications' mechanisms of action, potentially precluding unnecessary tests, and reducing duration of stay. Discussion: The endocannabinoid system is a complex and important regulator of stress response and allostasis, and it is occasionally overwhelmed from excessive cannabis use. Acute episodes of CHS may be precipitated by stress or fasting in chronic cannabis users who may have pre-existing abnormal hypothalamic-pituitary-adrenal axis feedback and sympathetic nervous system response. The reasons for this may lie in the physiology of the endocannabinoid system, the pathophysiology of CHS, and the pharmacologic properties of specific classes of antiemetics and sedatives. Treatment failure with standard antiemetics is common, necessitating the use of mechanistically logical sedating agents such as benzodiazepines and antipsychotics. Conclusion: Despite the increasing prevalence of CHS, there is a limited body of high-quality research. Benzodiazepines and antipsychotics represent logical choices for treatment of CHS because of their powerful sedating effects. Topical capsaicin holds promise based on a totally different pharmacologic mechanism. Discontinuation of cannabis use is the only assured cure for CHS.
Article
Background: There is limited published scientific data on vaping recreational drugs other than cannabis. A recent review suggested that 15% of people vaping cannabis have also vaped a synthetic cannabinoid receptor agonist (SCRA) and identified over 300 Internet reports of e-liquid manufacture of recreational drugs and/or new psychoactive substances (NPS). Aim: To determine the prevalence of use of electronic vaping devices for recreational drug and NPS delivery in the UK. Design: A voluntary online survey using a convenience sample of UK adult participants (aged 16 years old and over) identified by a market research company. Methods: Data was collected regarding demographics, smoking history, electronic vaping device history and recreational drug/NPS use and route of administration. Results: There were 2501 respondents. The mean (±SD) age was 46.2±16.8 years old. The commonest lifetime recreational drug used was Cannabis (818,32.7%). The majority of respondents had smoked (1545,61.8%) with 731 (29.2%) being current smokers. The most commonly used SCRA product was 'Spice Gold' (173,6.9%) and SCRA compound was ADB-CHMICA (48,1.9%). 861 (34.4%) had used an electronic vaping device; 340 (13.6%) having used them for recreational drug administration; 236 (9.4%) reporting current use. The commonest lifetime recreational drug to be vaped was cannabis (155,65.7%), with electronic cigarettes (230,48.2%) being the commonest reported route of SCRA compound administration. Conclusions: 9.4% of respondents currently use electronic vaping devices for recreational drug administration with 6.2% reporting lifetime cannabis vaping use. Further larger scale studies are required to help inform the appropriate treatment and primary prevention strategies.
Article
Background: Cannabis use is common in North America, especially among young people, and is associated with a risk of various acute and chronic adverse health outcomes. Cannabis control regimes are evolving, for example toward a national legalization policy in Canada, with the aim to improve public health, and thus require evidence-based interventions. As cannabis-related health outcomes may be influenced by behaviors that are modifiable by the user, evidence-based Lower-Risk Cannabis Use Guidelines (LRCUG)-akin to similar guidelines in other health fields-offer a valuable, targeted prevention tool to improve public health outcomes. Objectives: To systematically review, update, and quality-grade evidence on behavioral factors determining adverse health outcomes from cannabis that may be modifiable by the user, and translate this evidence into revised LRCUG as a public health intervention tool based on an expert consensus process. Search methods: We used pertinent medical search terms and structured search strategies, to search MEDLINE, EMBASE, PsycINFO, Cochrane Library databases, and reference lists primarily for systematic reviews and meta-analyses, and additional evidence on modifiable risk factors for adverse health outcomes from cannabis use. Selection criteria: We included studies if they focused on potentially modifiable behavior-based factors for risks or harms for health from cannabis use, and excluded studies if cannabis use was assessed for therapeutic purposes. Data collection and analysis: We screened the titles and abstracts of all studies identified by the search strategy and assessed the full texts of all potentially eligible studies for inclusion; 2 of the authors independently extracted the data of all studies included in this review. We created Preferred Reporting Items for Systematic Reviews and Meta-Analyses flow-charts for each of the topical searches. Subsequently, we summarized the evidence by behavioral factor topic, quality-graded it by following standard (Grading of Recommendations Assessment, Development, and Evaluation; GRADE) criteria, and translated it into the LRCUG recommendations by the author expert collective on the basis of an iterative consensus process. Main results: For most recommendations, there was at least "substantial" (i.e., good-quality) evidence. We developed 10 major recommendations for lower-risk use: (1) the most effective way to avoid cannabis use-related health risks is abstinence, (2) avoid early age initiation of cannabis use (i.e., definitively before the age of 16 years), (3) choose low-potency tetrahydrocannabinol (THC) or balanced THC-to-cannabidiol (CBD)-ratio cannabis products, (4) abstain from using synthetic cannabinoids, (5) avoid combusted cannabis inhalation and give preference to nonsmoking use methods, (6) avoid deep or other risky inhalation practices, (7) avoid high-frequency (e.g., daily or near-daily) cannabis use, (8) abstain from cannabis-impaired driving, (9) populations at higher risk for cannabis use-related health problems should avoid use altogether, and (10) avoid combining previously mentioned risk behaviors (e.g., early initiation and high-frequency use). Authors' conclusions: Evidence indicates that a substantial extent of the risk of adverse health outcomes from cannabis use may be reduced by informed behavioral choices among users. The evidence-based LRCUG serve as a population-level education and intervention tool to inform such user choices toward improved public health outcomes. However, the LRCUG ought to be systematically communicated and supported by key regulation measures (e.g., cannabis product labeling, content regulation) to be effective. All of these measures are concretely possible under emerging legalization regimes, and should be actively implemented by regulatory authorities. The population-level impact of the LRCUG toward reducing cannabis use-related health risks should be evaluated. Public health implications. Cannabis control regimes are evolving, including legalization in North America, with uncertain impacts on public health. Evidence-based LRCUG offer a potentially valuable population-level tool to reduce the risk of adverse health outcomes from cannabis use among (especially young) users in legalization contexts, and hence to contribute to improved public health outcomes.