Clinical Data For Use of Cannabis A Review

930189
review-article2020
AOPXXX10.1177/1060028020930189Annals of PharmacotherapyInglet et al
Review Article
Annals of Pharmacotherapy
Clinical Data for the Use of Cannabis-

1–35
© The Author(s) 2020
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DOI: 10.1177/1060028020930189
https://doi.org/10.1177/1060028020930189
Review of the Literature journals.sagepub.com/home/aop
Shannon Inglet, PharmD1 , Bradly Winter, PharmD1,

Sarah E. Yost, PharmD1, Sophia Entringer, PharmD1,
Anh Lian, PharmD1, Meryl Biksacky, PharmD1,
Renee D. Pitt, PharmD1, and Whitney Mortensen, PharmD, MBA1
Abstract
Objective: To compile and synthesize the available literature describing medical cannabis use across various disease
states. Data Sources: PubMed, EBSCO, and Google Scholar searches were conducted using MeSH and/or keywords.
Study Selection and Data Extraction: Studies were included if they described the use of cannabis-based products
and medications in the treatment of a predefined list of disease states in humans and were published in English. The
extraction period had no historical limit and spanned through April 2019. Data Synthesis: Evidence was compiled
and summarized for the following medical conditions: Alzheimer disease, amyotrophic lateral sclerosis, autism, cancer
and cancer-associated adverse effects, seizure disorders, human immunodeficiency virus, inflammatory bowel disease,
multiple sclerosis (MS), nausea, pain, posttraumatic stress disorder, and hospice care. Relevance to Patient Care
and Clinical Practice: Based on identified data, the most robust evidence suggests that medical cannabis may be
effective in the treatment of chemotherapy-induced nausea and vomiting, seizure disorders, MS-related spasticity, and
pain (excluding diabetic neuropathy). Overall, the evidence is inconsistent and generally limited by poor quality. The large
variation in cannabis-based products evaluated in studies limits the ability to make direct comparisons. Regardless of the
product, a gradual dose titration was utilized in most studies. Cannabis-based therapies were typically well tolerated, with
the most common adverse effects being dizziness, somnolence, dry mouth, nausea, and euphoria. Conclusions: As more
states authorize medical cannabis use, there is an increasing need for high-quality clinical evidence describing its efficacy
and safety. This review is intended to serve as a reference for clinicians, so that the risks and realistic benefits of medical
cannabis are better understood.
Keywords
cannabis, cannabidiol, marijuana, tetrahydrocannabinol, medical cannabis, medical marijuana, CBD, THC, EPIDIOLEX,
nabiximols, Sativex, dronabinol, Marinol, Syndros, nabilone, Cesamet, marihuana
Background Objective
Under US federal law, cannabis remains a Schedule I drug; The objective of this review was to compile and synthesize
however, as of June 2019, 33 states have passed legislation the available literature describing the use of cannabis-based
allowing cannabis use for a variety of qualifying medical medications and products across a variety of disease states.
conditions.1,2 Apart from the legal entanglement associated
with medical cannabis, it has also been unclear what avail-
able evidence describes its efficacy and safety. Patients are
more frequently requesting information about medical can- 1
Intermountain Healthcare, Taylorsville, UT, USA
nabis from their providers and pharmacists.3 Thus, it is Corresponding Author:
imperative that health care professionals are equipped with Shannon Inglet, Drug Information Service, Intermountain Healthcare,
accurate and current information in order to make evidence- 4393 South Riverboat Road, Suite 100, Taylorsville, UT 84123, USA.
based decisions. Email: Shannon.Inglet@imail.org
2 Annals of Pharmacotherapy 00(0)
Data Sources application for nabiximols.7,8,13 Although terminology is

nuanced, these drugs are referred to as cannabis-based
Primary literature was collected via the databases PubMed, medications in this review. Currently, cannabis and canna-
EBSCO, and Google Scholar using MeSH and/or keywords: binoids are also supplied in a wide variety of nonstandard-
“cannabis,” “medical marijuana,” “cannabidiol,” and “tetra- ized medicinal dosage forms, including tablets, capsules,
hydrocannabinol,” in combination with the qualifying condi- concentrated oils, topical preparations, unprocessed flower
tion and its synonyms, as appropriate. Tertiary references buds, and resins and are generally referred to as cannabis-
such as The Health Effects of Cannabis and Cannabinoids based products in this review.14,15 The term medical can-
report from the National Academies of Sciences, Engineering, nabis is used broadly in this review to encompass both
and Medicine, professional organization guidelines, and aca- medications and products. The authors of this review chose
demic websites were also utilized, as applicable. to include studies evaluating both cannabis-based products
as well as cannabis-based medications to provide the most
Study Selection and Data Extraction comprehensive and inclusive literature summary possible.
Additionally, many peer-reviewed publications and meta-
Studies were included in the review if they described the analyses have compared cannabis-based products with
use of a cannabis-based product and/or a cannabis-based cannabis-based medications, so there is an historical prec-
medication (eg, dronabinol, nabilone, nabiximols, canna- edent as well. When comparing cannabis-based products,
bidiol [CBD] oral solution) in the treatment of a pre- the authors acknowledge that there may be differences in
defined list of disease states. The predefined list was quality, composition, and potency that are unavoidable but
based on the most common disease states included in should be considered when drawing conclusions. Table 2
most states’ medical cannabis legislation.4 Case reports describes all dosage forms and strengths of medical can-
and phase II studies were considered in the overall evi- nabis evaluated in the literature, by disease state.
dence synthesis for disease states lacking more robust
evidence. Meta-analyses, randomized controlled trials,
observational studies, and retrospective studies were Clinical Evidence Summary for
preferentially included in this review and are summarized Cannabis in Select Disease States
in Table 1. The extraction period had no early historical
limit and spanned through April 2019. Articles included Alzheimer Disease
were limited to those in the English language and studies Although no data were identified suggesting that medical
conducted in humans. cannabis can modify, slow, or cure Alzheimer disease
(AD), some published clinical data show that medical can-
Data Synthesis nabis may improve dementia-related neuropsychiatric
symptoms secondary to AD (eg, agitation, anorexia-associ-
Dosage Forms ated weight loss, nighttime disturbances).16-27 A single
Cannabis has been utilized as a medical treatment for mil- observational study investigated the efficacy of cannabis
lennia; however, the pharmacology has only been studied oil (plant extract containing 1.65% THC) for managing
in recent decades.5 More than 100 different plant-derived behavioral and psychological symptoms of dementia in 11
cannabinoids have been identified, with cannabidiol (CBD) hospitalized AD patients and found significantly decreased
and tetrahydrocannabinol (THC) considered to be the most Neuropsychiatric Inventory scores from baseline to week 4
pharmacologically relevant because of their effects on the (44.4 to 12.8; P < 0.01) but no significant change in weight
endogenous cannabinoid system.5 Cannabidiol is a non- or Mini-Mental Status Examination scores.16 A recent
psychoactive component of cannabis, whereas THC is meta-analysis included 6 randomized, placebo-controlled
responsible for the euphoric or intoxicating effects. A trials in AD patients who received oral THC, dronabinol, or
higher THC:CBD ratio is associated with more prominent nabilone for the management of dementia-related aggres-
psychoactive symptoms, whereas a lower THC:CBD ratio sion and agitation.17 The authors found no significant
has more sedative effects.5 reduction in agitation among patients receiving cannabis-
To date, 3 CBD- and THC-based medications have been based medications or THC compared with patients receiv-
approved by the US Food and Drug Administration (FDA): ing placebo (standardized mean difference [MD] = −0.69;
dronabinol (Marinol, Syndros), nabilone (Cesamet), and P = 0.1).17 Overall, evidence for the management of
cannabidiol oral solution (Epidiolex).5-12 A fourth medica- dementia-related neuropsychiatric symptoms with medical
tion, nabiximols (Sativex), is an oromucosal spray com- cannabis in AD is equivocal.
prised of THC and CBD in a 1:1 ratio that is available in Similarly, some clinical evidence suggests that medical
several countries outside the United States, though the cannabis may be safe and well tolerated in AD patients,17-24
FDA recently accepted an Investigational New Drug whereas other evidence suggests that medical cannabis
Table 1. Literature Describing Cannabis Use and Clinical Evidence for Medical Cannabis in Various Disease States.a
Study Design Duration n Interventions Primary end point results
Alzheimer disease
Ruthirakuhan et al,17 MA NA 6 Trials; • Dronabinol 2.5 mg PO once daily • No significant reduction in agitation (SMD = −0.69; 95% CI = −1.5 to
2019 n = 143 • Dronabinol 2.5 mg PO bid 0.13)
• Nabilone 1.6 mg PO daily • No significant difference in neuropsychiatric symptoms or BMI
• THC 0.75 mg PO bid • Significantly more sedation noted with cannabinoids (RR = 1.73; 95% CI
• THC 1.5 mg PO bid 1.02 to 2.93)
• THC 1.5 mg PO tid
• Placebo
van den Elsen et al,18 DB, PC, C, RCT 3 Days 18 • THC PO 1.5 mg tablet bid then placebo • No clinically important differences observed in gait, dynamic balance, and
2017 PO bid static balance
• Placebo PO bid then THC PO 1.5 mg • Statistically significant differences in static balance and gait between THC
tablet bid and placebo indicate THC may have adverse effects on balance and gait at
higher doses
Shelef et al,16 2016 OL, PD 4 Weeks 11 Cannabis oil bid titrated by 2.5 mg every 2 Significant decrease in NPI score from baseline (44.4) to week 4 (12.8,
days to a maximum of 7.5 mg bid P < 0.01)
van den Elsen et al,20 DB, MC, PC, C, 3 Weeks 50 • THC 1.5 mg PO tablet tid • No significant improvement in NPI score in THC group compared with
2015 RCT • Placebo tablet PO tid placebo group (ΔNPItotal: 3.2; 95% CI = −3.6 to 10)
• No significant differences in activities of daily living, CCGIC scores, CMAI
scores, or quality of life
van den Elsen et al,19 DB, MC, PC, C, 12 Weeks 22 Treatment period A No significant differences in NPI score, CMAI score, or caregiver burden
2015; Ahmed RCT • THC 0.75 mg oral tablet bid ×3 days among low-dose THC, high-dose THC, and placebo
et al,21 2015 • Placebo oral tablet bid ×3 days
Treatment period B
• THC 1.5 mg PO bid ×3 days
• Placebo PO bid ×3 days
Woodward et al,22 RCS, SC 4 To 7 days 40 Dronabinol 7.03 mg/d • Significant improvement in PAS scores (9.68 vs 5.25, P < 0.0001) and
2014 CGI scores (5.15 vs 3.75, P < 0.0001) from pre–dronabinol treatment to
post–dronabinol treatment
• No difference in GAF scores or change in weight pretreatment and
posttreatment
Walther et al,23 DB, C, PC, SC, 4 Weeks 2b • Dronabinol 2.5 mg oral capsule • Initial decline in nocturnal motor activity observed with dronabinol,
2011 RCT every evening overall decline in NPI score from baseline to week 4
• Placebo oral capsule every evening • Improved circadian rhythms reported during dronabinol treatment,
assessed with NPCRA
Walther et al,24 OL, PD, SA, SC 2 Weeks 6 Dronabinol 2.5 mg oral capsule every • Significant reduction in nocturnal motor activity from baseline (34 260
2006 evening activity counts) to week 2 (10 790 activity counts, P = 0.028)
• Significant reduction in NPI score from baseline to week 2 (scores not
reported, P = 0.027)
• No significant impact on anxiety, apathy, delusions, hallucinations, or
augmentative sedative medication use observed from baseline to week 2
Volicer et al,25 1997 C, DB, PC, RCT 6 Weeks 12 • Dronabinol 2.5 mg oral capsule bid • Body weight increased for all participants over 12 weeks
• Placebo oral capsule bid • Decreased agitation (decreased CMAI scores) observed during each
dronabinol treatment period; decreased agitation was sustained during the
placebo treatment period
(continued)
3
4
Table 1. (continued)
Amyotrophic lateral sclerosis

Riva et al,37 2019 DB, MC, PC, RCT 12 Weeks 60 6-Week blinded phase
• Nabiximols oromucosal spray, titrated Significantly improved MAS score (adjustedc MD = −0.32; 95% CI = −0.57
• Placebo oromucosal spray, titrated to −0.069) and NRS pain score (adjustedc MD = −1.15; 95% CI = −2.1
to −0.21)
6-Week open-label extension
Nabiximols oromucosal spray, titrated Anecdotal improvements in mean MAS score and other outcomes (eg, NRS
pain, NRS spasticity, NRS spasm frequency) noted for patients originally
assigned to placebo
Weber et al,34 2010 PC, SC, C RCT 6 Weeks 22 • Dronabinol (THC) oil 5 mg PO bid • No difference in VAS cramp intensity (MD = 0.24; 95% CI = −0.32 to
• Placebo oil PO bid 0.81)
• No differences in appetite, depression, fasciculation intensity, number
of cramps daily, number of cramps nightly, quality of life, or sleep were
observed
Autism spectrum disorder
Barchel et al,42 PCS 66 Days (median) 53 CBD and THC 20:1 oil SL daily at dosages Overall improvement (hyperactivity symptoms, self-injury, rage attacks,
2019d of CBD 16 mg/kg (max 600 mg) and sleep problems anxiety) in 74.5%, no change in 21.6%, worsening in 3.9%
THC 0.8 mg/kg (max 40 mg)
Schleider et al,43 PCS 6 Months 188 CBD and THC 20:1 oil sublingual tid with • Average of 6 symptoms reported at baseline, with the most common
2019d each 0.05-mL drop containing CBD being restlessness at 90.4%, rage attacks at 79.8%, and agitation at 78.7%
15 mg (30%) and THC 0.75 mg (1.5%) • At 6 months, 82.4% continued active treatment in which 30.1% reported
titrated to effect and tolerability up to a significant improvement, 53.7% moderate, and 8.6% no change
max of 20 drops tid
Aran et al,44 2018d RCS NA 60 CBD and THC 20:1 oil SL bid to tid CGI of Change scale:
starting at 1 mg/kg/d titrated to effect • 61% Reported improvement in behavioral outbreaks
and tolerability up to CBD of 10 mg/kg/d • 47% For communication
• 39% For anxiety
• 33% For stress and disruptive behavior
Kuester et al,45 RCS ≥3 Months 21 • CBD extracts SL given ≥3 months 66.7% Of patients had significant improvement in CGI of Improvement and
2017d • 71.5% Of patients received balanced APSI scores
CBD:THC extracts; 19% high-CBD and
9.5% high-THC extracts
Cancer
Häuser et al,66 2019 MA ≥2 Weeks 4 RCTs Medical cannabis, cannabis-based medicines ≥50% Pain relief (4 studies, n = 1333)
(n = 1539 (dronabinol, nabiximols), and synthetic • Cannabis-based medicines 11.8%
cannabinoids (nabilone) compared with • Placebo 9.7%
any active comparator or placebo • Cannabis-based vs placebo, P = 0.82
Patient impression to be very much improved (2 studies, n = 710)
• Cannabis-based medicines 27.1%
• Placebo 20.7%
• Cannabis-based vs placebo, P = 0.04, NNT 16
Mücke et al,67 2018 MA Various 8 Studies • Herbal cannabis, plant-based or synthetic • ≥30% Pain reduction (2 studies, n = 537)
(n = 1561) cannabinoids in every form of application • Cannabinoid 30.5%
and dose • Placebo 22.7%
• Placebo or active control • Cannabinoid vs placebo, P = 0.07
(continued)
57
Brisbois et al, 2011 DB, MC, PC, RCT 18 Days 46 Initial (3 days) • Significantly higher Taste and Smell Survey scores with dronabinol (2.5) vs
• Dronabinol 2.5 mg daily placebo (1.8), P = 0.018
• Placebo daily • Significantly higher average premeal SLIM score with dronabinol (60.7) vs
Maintenance (15 days) placebo (50.9), P = 0.05
• Dronabinol 2.5 mg bid with titration • No difference in posttreatment caloric intake between groups
(max dose: 20 mg/d)
• Placebo bid
Jatoi et al,56 2002 DB, MC, RCT NA 469 • MAc liquid suspension 800 mg daily + • Increased appetite significant for MAc (75%) vs dronabinol (49%; P =
placebo capsules 0.0001) but not combination (66%) vs MAc (P = 0.17)
• Dronabinol capsules 2.5 mg bid + liquid • Physician-reported 10% weight increase significant for MAc (14%) vs
placebo dronabinol (5%; P = 0.009) but not combination (11%) vs MAc (P = 0.49)
• Dronabinol capsules 2.5 mg bid + MAc
liquid suspension 800 mg daily
Nelson et al,58 1994 SC, PCS 4 Weeks 18 • Dronabinol 2.5 mg PO tid No appetite improvement in 26.3% (5), slight improvement in 55.6% (10),
• Age > 65 years: dronabinol 2.5 mg bid major improvement in 15.8% (3)
for 3 days, then 2.5 mg tid, if tolerated
Plasse et al,59 1991 OL, MC, RCT NA 42 • Dronabinol 2.5 mg daily, 2.5 mg bid, 5 mg Significant improvement in weight change and appetite change (on VAS) for
daily, 5 mg bid all dronabinol doses vs placebo
• Placebo
Anderson et al,62 RCS ≥4 Months 1120 THC:CBD ratios categorized as high ≥30% Symptom improvement within 4 months of first purchase
2019 (>1:1) with the following routes of
administration: enteral, inhaled/vaporized,
and oromucosal products
Cannabis-In- DB, MC, PC, RCT 6 Weeks 243 • Cannabis extract (THC 2.5 mg, CBD 1 • No significant appetite change from baseline to week 6 on VAS between
Cachexia-Study- mg) capsules bid cannabis extract vs placebo (P = 0.46) or THC vs placebo (P = 0.95)
Group et al,60 • THC 2.5 mg capsules bid • No significant quality-of-life change from baseline between cannabis
2006 • Placebo capsules bid extract vs placebo (P = 0.80), THC vs placebo (P = 0.43), or cannabis
extract vs THC (P = 0.90)
Turcott et al,61 2018 DB, PC, RCT 8 Weeks 47 Nabilone 1 mg daily vs placebo No significant change in Anorexia/Cachexia Scale, VAS for loss of appetite
and weight loss, or weight from baseline between nabilone vs placebo
Bar-Sela et al,75 2013 PCS 6 To 8 weeks 211 Medical cannabis (specific dosage form and Significant improvement in pain symptoms between first and second
route not specified) interview after taking medical cannabis (n = 106), P < 0.001
Turcott et al,61 2018 DB, PC, RCT 8 weeks 47 • Nabilone 1 mg daily Significant decrease in pain score on HRQoL questionnaire with nabilone
• Placebo daily from baseline (50) to 8 weeks (37), P = 0.016; no difference in pain score
with placebo from baseline to 8 weeks
Maida et al,74 2008 PCS NA 112 • Nabilone 1 mg/d Significantly lower pain score with nabilone (3) vs untreated (5.5), P < 0.001
• Nabilone 1-2 mg/d
• Nabilone >2 mg/d
• Untreated
Lichtman et al,68 DB, MC, PC, RCT NA 397 • Nabiximols oromucosal spray No difference in percentage improvement in NRS pain score from baseline
2018 • Placebo with nabiximols (10.7%) vs placebo (4.5%), P = 0.854
Fallon et al,69 2017 DB, PC, MC, RCT 5 Weeks 399 • Nabiximols oral mucosal spray No difference in percentage improvement in average pain NRS score from
(study 1) • Placebo baseline to end of treatment with nabiximols (7.2%) vs placebo (9.5%), P
= 0.274
5
(continued)
6
69
Fallon et al, 2017 SB, PC, MC, RCT 5 Weeks and 10 406 Part A: SB titration No difference in mean change in NRS pain score from baseline to end of
(study 2) days • Nabiximols oral mucosal spray treatment with nabiximols (0.5) vs placebo (0.5), P = 0.917
Part B: DB, RCT
• Nabiximols oral mucosal spray
• Placebo
Lynch et al,73 2014 DB, PC, C, MC, 10 Weeks 18 • Nabiximols oromucosal spray Significant decrease in change of NRS-PI from baseline with nabiximols
RCT • Placebo (−2.6) vs placebo (0.6), P < 0.001
Portenoy et al,70 DB, PC, MC, RCT 5 Weeks 360 • Nabiximols oromucosal spray No difference in ≥30% pain reduction with nabiximols vs placebo, P = 0.59
2012 • Placebo
Johnson et al,71 2010 MC, PC, DB, RCT 2 Weeks 177 • Nabiximols oromucosal spray Change in NRS from baseline significant for nabiximols (−1.37) vs placebo
• THC 2.7 mg oromucosal spray (−0.69), P = 0.014, but not THC (−1.01) vs placebo, P = 0.245
• Placebo oromucosal spray
Epilepsy and seizure disorders
Lattanzi et al,77 MA Variable 4 RCTs Cannabidiol solution PO 5, 10, or 20 mg/ • Pooled MD in change in seizure frequency between CBD 10 mg/kg/d vs
2018d (n = 550) kg/d divided bid placebo was 19.5% (95% CI = 8.1 to 31; P = 0.001)
Placebo solution PO bid • The difference in change in seizure frequency between CBD 20 mg/kg/d vs
placebo was 19.9% (95% CI = 11.8 to 28.1; P < 0.001)
• A 50% reduction in all seizure types occurred in 37.2% and 21.2% of
patients receiving CBD 20 mg/kg/d and placebo, respectively (RR = 1.76;
95% CI = 1.07 to 2.88; P =0.025)
Devinsky et al,82 PCS, OL, MC ≥10 Weeks (up 46 Cannabidiol oral solution (Epidiolex) 5 mg/ • Median seizure frequency reduction at 12 weeks was 51.4% (IQR = 9% to
2018d to 48 weeks) kg/d to a maximum of 50 mg/kg/d 85%; P = 0.00001) and 59.1% (IQR = 14% to 86%; n = 27) at 48 weeks
• At weeks 12 and 48, 50% and 57% of patients had a 50% or greater
reduction in seizure frequency, respectively
Devinsky et al,78 RCT, DB, MC, PC 24 Weeks 225 • Cannabidiol oral solution (Epidiolex) Reduction in frequency of drop seizures with cannabidiol: estimated median
2018d titrated to 20 mg/kg/d difference of 21.6 percentage points (95% CI = 6.7 to 31.2; P = 0.005)
• Cannabidiol oral solution (Epidiolex) between 20-mg cannabidiol and placebo and estimated median difference
titrated to 10 mg/kg/d of 19.2 percentage points (95% CI = 7.7 to 31.2; P = 0.002) between 10-
• Placebo oral solution mg cannabidiol and placebo
Thiele et al,79 2018d RCT, DB, MC, PC 24 Weeks 171 • Cannabidiol oral solution (Epidiolex) Reduction in frequency of drop seizures with cannabidiol; estimated median
titrated to 20 mg/kg/d difference between treatment groups was −19.45 percentage points (95%
• Placebo oral solution CI = −33.05 to −4.68; P = 0.0096) during 12-week maintenance period
Chen et al,83 2018d PCS, OL, MC 12 Weeks 40 Cannabidiol oral solution (Epidiolex) No difference in hospital admission rates between before treatment and
titrated to 25 mg/kg/d during the study (0.29 vs 0.39 admissions/patient/month; P = 0.28)
Szaflarski et al,84 OL, MC 3 Years 607 Cannabidiol oral solution (Epidiolex) 52% Of patients had ≥50% reduction in convulsive seizures at week 12
2018d titrated to 25 or 50 mg/kg/d compared with baseline
Devinsky et al,80 RCT, DB, MC, PC 13 Weeks 34 • Cannabidiol oral solution (Epidiolex) No obvious pharmacokinetic effects of cannabidiol on valproate,
2018d titrated to 5-, 10-, or 20-mg/kg/d topiramate, stiripentol, or levetiracetam; all 3 doses of cannabidiol led
• Placebo oral solution to a pharmacokinetic interaction with clobazam, causing an increase of
N-desmethylclobazam (may contribute to increase in antiseizure activity,
sedation, and fatigue)
Devinsky et al,81 RCT, DB, MC, PC 24 Weeks 120 • Cannabidiol oral solution (Epidiolex) Significant decrease in convulsive-seizure frequency with cannabidiol vs
2017d titrated to 20 mg/kg/d placebo: adjusted median difference of −22.8 percentage points (95% CI =
• Placebo oral solution −41.1 to −5.4; P = 0.01)
(continued)
Devinsky et al,85 PCS, OL, MC 16 Weeks 162 Cannabidiol oral solution (Epidiolex) Decrease in frequency of median monthly motor seizure by −36.5% from
2016d titrated to 25 or 50 mg/kg/d baseline; reduction of ≥50% in motor seizures in 39% of patients at end
of 12 weeks
Hess et al,86 2016d OL, MC 12 Months 18 Cannabidiol oral solution (Epidiolex) at 5 Median seizure frequency decreased from 14.9 (IQR = 5.7 to 22) at
mg/kg/d to a max of 50 mg/kg/d baseline to 8 (IQR = 3.7 to 47.7)
Rosenberg et al,87 PCS, OL, MC 12 Weeks 213 Cannabidiol oral solution (Epidiolex) + Median reduction in total seizures at 12 weeks: 54%, with 51% reduction in
2015d Existing AED regimen convulsive seizures
Geffrey et al,88 PCS, OL, SC 36 Weeks 13 Cannabidiol oral solution (Epidiolex) 5 mg/ 9 Of 13 (70%) patients achieved a 50% or greater reduction in seizure
2015d kg/d titrated to a goal of 25 mg/kg/d + frequency, despite decreases in clobazam doses
stable clobazam dose
Hausman-Kedem PCS, OL, SC 18 Months 57 CBD and THC (20:1) oil SL 2 to 5 mg/ >56% Of patients had ≥50% reduction in seizure frequency from baseline
et al,89 2018d (median) kg/d + current AED regimen; 17 patients
transferred to inhaled cannabis (either
alone or in combination with oil)
Porcari et al,90 2018d RCS, SC 10 Years 176 • CBD Following CBD or clobazam initiation, ≥50% reduction in seizure frequency
• clobazam in 33% of CBD group, 44% of CBD + clobazam group, and 38% of
• CBD + clobazam clobazam group
10 Different CBD products utilized
Tzadok et al,95 RCS, MC 3 To 12 months 74 CBD and THC (20:1) oil SL with CBD Most patients (89%) had some reduction in seizure frequency: 18% had a
2016d dose ranging from 1 to 20 mg/kg/d 75% to 100% reduction, 34% had a 50% to 75% reduction, 12% had a 25%
(according to seizure response and AEs) to 50% reduction, 26% had a <25% reduction
Human Immunodeficiency Virus (HIV)/Acquired Immune Deficiency Syndrome (AIDS)
Farooqui et al,132 MA Variable 9 Studies Marijuana users vs nonusers Marijuana use not associated with increased prevalence or progression of
2019 hepatic fibrosis in patients with HCV or HCV and HIV coinfection
Goldenberg et al,128 MA Variable 20 Studies Marijuana users vs nonusers No significant difference in physical or mental HRQoL between marijuana
2017 with 11 users vs nonusers, but decreased mental HRQoL with marijuana in HIV
RCTs patients was noted
Andreae et al,109 Bayesian individual Variable 5 RCTs • Smoked cannabis Greater proportion of patients achieved >30% reduction in pain with
2015 patient data MA • Placebo inhaled cannabis vs placebo; OR = 3.2 (95% CRI = 1.6 to 7.2), NNT =
5.6 (95% CRI = 3.4 to 13.7)
Phillips et al,111 2010 MA Variable 14 RCTs Smoked cannabis vs placebo in 2 RCTs Greater proportion of patients achieved >30% reduction in pain using VAS
data from both RCTs under ITT analysis for smoked cannabis (50.8%) vs
placebo (24.6%) and NNT of 3.38 (95% CI = 2.2 to 7.5)
Ellis et al,110 2009 DB, C, PC, SC, 10 Days 28 Smoked cannabis (1%-8% THC) vs placebo Greater pain reduction with cannabis than placebo, with median difference
RCT of 3.3 out of 20 points (P = 0.016)
Abrams et al,108 DB, PC, SC, RCT 5 Days 50 Smoked cannabis (3.56% THC) vs identical 34% Reduction in VAS pain rating with smoked cannabis vs 17% with
2007 placebo cigarette tid as tolerated placebo (P = 0.03); 52% reported >30% reduction in pain intensity
with cannabis vs 24% with placebo (P = 0.04; NNT = 3.6); 72% median
reduction in VAS pain rating after the first cigarette with smoked cannabis
vs 15% with placebo (P < 0.001)
Abrams et al,117 DB, PC, SC, RCT 21 Days 62 Smoked cannabis (3.95% THC), oral No significant difference in viral load between cannabis, dronabinol, and
2003 dronabinol 2.5 mg, or placebo capsule up placebo: −15% (95% CI = −50% to 34%) for smoked cannabis relative to
to tid before meals placebo; 8% (95% CI = −37% to 37%) for dronabinol relative to placebo
Kosel et al,270 2002 RCT 14 Days 62 Smoked cannabis (3.95% THC), oral No significant change in ART levels at day 14 in patients given cannabis; did
dronabinol 2.5 mg, or placebo capsule tid not change significantly in magnitude
7
(continued)
8
Inflammatory bowel disease (Crohn’s disease [CD], ulcerative colitis [UC])

Irving et al,146 2018 MC, DB, PC, RCT 10 Weeks 60 CBD oral capsules 100 to 500 mg daily vs No difference in clinical remissione rate vs placebo (RR = 0.94; 95% CI =
placebo capsule 0.39 to 2.25)
Kafil et al,141 2018 DB, PC, RCT 8 Weeks 32 Cannabis cigarettes vs placebo cigarettes Greater improvement in DAI compared with placebo (MD = −4; 95% CI =
−5.98 to −2.02)
Naftali et al,147 2017 SC, DB, PC, RCT 8 Weeks 19 SL cannabis oil vs placebo oil No difference in clinical remission rate compared with placebo (RR = 1.2;
95% CI = 0.36 to 3.97)
Kafil et al,140 2018 DB, PC, RCT 8 Weeks 50 Cannabis oil vs placebo oil Greater improvement in CDAI vs placebo (MD = −94; 95% CI = −148.86
to −39.14)
Improved SF-36 survey score vs placebo (MD = 16.4; 95% CI = 5.72 to
27.08)
Naftali et al,142 2013 SC, DB, PC, RCT 8 Weeks 21 Cannabis cigarettes vs placebo cigarettes • No difference in clinical remission rate compared with placebo (RR =
4.55; 95% CI = 0.63 to 32.56)
• Higher clinical response rate (at least a 100-point decrease in CDAI from
baseline) in cannabis group compared with placebo group (RR = 2.27;
95% CI = 1.04 to 4.97)
Naftali et al,143 2013 RCT, PC 8 Weeks 30 Cannabis cigarettes vs placebo cigarettes • CD patients: significantly greater decrease in CDAI in cannabis group
(−219) compared with placebo (−67, P < 0.05)
• UC patients: greater decrease in UCAI in cannabis group (−7) compared
with placebo (−3, P = NR)
Lahat et al,144 2012 OL, SA, PD 3 Months 13 Cannabis cigarettes, 3 inhalations per dose • CD patients: improved HBI from baseline (11.36) to 3 months (5.72, P =
as needed for pain 0.001)
• UC patients: slight improvement in partial Mayo score from baseline (6)
to 3 months (5)
Naftali et al,145 2011 R, SC 3 Months to 9 30 Cannabis inhaled or ingested at variable Significant decrease in HBI, comparing before cannabis use with after
years doses as needed for pain cannabis use (14 vs 7, P < 0.001)
Multiple sclerosis and spasticity
Flachenecker O, MC, PD 3 To 4 months 276 Nabiximols (Sativex) oromucosal spray Relief of spasm at 1 month: 74.6% (per specialist assessment)
et al,164 2014 Mean reduction in spasticity score (0 to 10 scale): 6.1 (±1.8) to 5.2 (±2
(MOVE-2) points)
Flachenecker O, MC, PD 12 Months 52 Nabiximols (Sativex) oromucosal spray Change in mean spasticity per NRS (0 to 10) significantly improved over
et al,165 2014 time:
(MOVE-2 follow- • Baseline: 6.0 ± 1.8
up) • 1 Month: 4.8 ± 1.9
• 12 Months: 4.5 ± 2.0
Langford et al,161 • Phase A: phase 30 Weeks • Phase A: • Experimental: nabiximols (Sativex) Primary outcome (phase A):
2013 III, DB, PC, MC 339 oromucosal spray • No difference in ≥30% of mean pain NRS score improvement from
for 14 weeks • Phase B: 42 • Control: placebo baseline with nabiximols (50% responders) vs placebo (45% responders),
followed by OR = 1.31 (95% CI = 0.84 to 2.04; P = 0.234)
• Phase B: OL Primary outcome in withdrawal phase (phase B):
for 12 weeks • Nabiximols (24%)
followed by • Placebo (57%)
4 weeks of a • Favors nabiximols (P = 0.04)
DB withdrawal
phase
(continued)
Zajicek et al,166 2012 DB, PC, MC, RCT 12 Weeks 279 OCE vs placebo Primary outcome:
(MUSEC) • Increased improvement in CRS measuring muscle stiffness with OCE
(29.4%) vs placebo (15.7%) compared with baseline; OR = 2.26 and
1-sided P = 0.004 (95% CI = 1.24 to 4.13)
Corey-Bloom DB, PC, C, RCT 3 Days 30 Smoked cannabis once daily vs placebo Smoked cannabis reduced spasticity per the MAS by 2.75 points (P <
et al,167 2012 cigarette once daily 0.0001)
Novotna et al,169 Phase III, DB, PC, 12 Weeks + 241 Nabiximols (Sativex) oromucosal spray vs Improvement in mean spasticity NRS (0 to 10) difference compared with
2011 MC, 2-week follow- placebo baseline with nabiximols (improved 0.04 units from baseline; score of
up 3.87) vs placebo (deterioration of 0.81 from baseline; score of 3.92);
difference between groups: 0.84 points (95% CI = −1.29 to −0.40; P =
0.0002) in favor of nabiximols
Wade et al,177 2010 MA Variable 666 • Nabiximols (Sativex) oromucosal spray Less spasticity as measured by a VAS (0 to 100) or NRS (0 to 10) with
• Placebo nabiximols (−1.30) vs placebo (−0.97), −0.32 treatment difference (95% CI
= −0.61 to −0.04; P = 0.026)
Collin et al,170 2010 DB, PC, MC, RCT 14 Weeks • 337 (ITT) • Nabiximols (Sativex) oromucosal spray No significant improvement in mean spasticity NRS (0 to 10) difference with
• 266 (PP) • Placebo nabiximols (decrease of 1.05 points from mean 6.77) vs placebo (decrease
of 0.82 from mean 6.48) in ITT population (difference = −0.23; P = 0.219)
but significant in PP population (difference = −0.46; P = 0.035)
Wade et al,174 2003 Phase II, DB, PC, 8 Weeks 24 • THC 2.5 mg:CBD 2.5 mg per SL spray VAS scores improved compared with placebo:
C, RCT • THC 2.5 mg per SL spray • THC:CBD improved muscle spasm and sleep
• CBD 2.5 mg per SL spray • THC improved pain, muscle spasm, spasticity, and appetite
• Placebo • CBD improved pain
Kavia et al,158 2010 DB, PC, MC, RCT 10 Weeks 135 • Nabiximols (Sativex) oromucosal spray No difference in reduction of urinary incontinence episodes (per daily
• Placebo patient diaries) between treatment groups
Freeman et al,159 MC, PC, RCT 15 Weeks 255 • OCE 1.25 mg per capsule • Reduction in urge incontinence episodes from baseline: OCE (38%); THC
2006 • THC 2.5 mg oral per capsule, titrated up (33%); placebo (18%; P < 0.01)
to tolerance • Treatment effect (ie, reduction in episodes) of experimental groups vs
• Placebo placebo: OCE (25%; P = 0.005); THC (19%; P = 0.039)
Collin et al,168 2007 DB, PC, MC RCT 6 Weeks 184 • Nabiximols (Sativex) oromucosal spray Larger change in patient-reported spasticity NRS (0 to 10) after 6 weeks
• Placebo with nabiximols vs placebo (0.52 points in favor of nabiximols (95% CI =
−1.029 to −0.004; P = 0.048)
Brady et al,160 2004 OL 8 Weeks 15 • THC 2.5 mg:CBD 2.5 mg per SL spray • Reduction in number of incontinence episodes (P < 0.05), frequency of
• THC 2.5 mg per SL spray episodes (P < 0.05), and sense of urgency (P < 0.05) with THC:CBD
compared with baseline
• Spasticity, pain, and difficulty sleeping improved with THC only (P < 0.05)
Rog et al,163 2005 DB, PC, SC, RCT 5 Weeks 64 • THC 2.7 mg:CBD 2.5 mg delivered via Larger reduction in mean intensity of pain per NRS-11 compared with
oromucosal spray baseline with THC:CBD −2.7 (95% CI = −3.4 to −2.0) vs placebo −1.4
• Placebo (95% CI = −2.0 to −0.8), P = 0.005
Zajicek et al,171 2003 DB, PC, MC, RCT 15 Weeks 630 • Oral THC 2.5 mg No significant differences (based on mean reduction) in overall spasticity
(CAMS study) • OCE THC 2.5 mg:CBD 1.25 mg score, as measured by the Ashworth Spasticity Scale for OCE vs placebo
• Placebo (0.32, 95% CI = −1.04 to 1.67) or THC vs placebo (0.94, 95% CI = −0.44
to 2.31)
(continued)
9
10
172
Zajicek et al, 2005 DB, MC, RCT 12 Months 502 • Oral THC 2.5 mg Significant mean reduction in overall spasticity score from baseline, as
• OCE THC 2.5 mg:CBD 1.25 mg measured by the Ashworth Spasticity Scale for THC:CBD 1.82 (8.12),
• Placebo THC 0.10 (7.25), and placebo −0.23 (7.87); P = 0.04
Svendsen et al,162 DB, PC, C, RCT 3 Weeks (15 to 24 • Dronabinol 2.5 mg PO daily to 5 mg PO Significant reduction in median spontaneous pain intensity per NRS for
2004 21 days) twice daily dronabinol (NRS = 4) vs placebo (NRS = 5), P = 0.02; difference
• Placebo between groups: −0.6 (95% CI = −1.8 to 0)
Vaney et al,173 2004 DB, PC, C RCT 2 Weeks 50 THC 2.5 mg:CBD 0.9 mg oral vs placebo • No statistical differences in Ashworth Spasticity Scale, digit span test,
auditory test, patient-reported spasms, RMI, 10-m Timed Walk, or 9-Hole
Peg Test when compared with baseline for ITT analysis
• Significant improvements in spasm frequency (P = 0.013) and RMI (P =
0.01) when compared with baseline for PP analysis
Wade et al,175 2004 DB, PC, MC, RCT 6 Weeks 160 • Nabiximols (Sativex) oromucosal spray No significant difference in mean VAS for patient’s self-chosen most
• Placebo troublesome symptom between nabiximols and placebo
Nausea and vomiting
Smith et al,207 2015 MA Variable 23 RCTs • Cannabinoids • Absence of N: placebo 3%, cannabinoids 6%, RR = 2 (0.2 to 21)
• Placebo • Absence of V: placebo 6%, cannabinoids 34%, RR = 5.7 (2.6 to 12.6)
• Absence of N and V: placebo 11%, cannabinoids 32%, RR = 2.9 (1.8 to
4.7)
Rocha et al,182 2008 MA Variable 30 RCTs Substances derived from Cannabis sativa • No significant difference in antiemetic efficacy for dronabinol over placebo
and/or smoked cannabis (n = 185; RR = 0.47; 95% CI = 0.19 to 1.16)
• Dronabinol demonstrated significantly more antiemetic efficacy than
neuroleptics (n = 325; RR = 0.67; 95% CI = 0.47 to 0.96; NNT = 3.4)
• No significant difference in antiemetic efficacy for nabilone over
neuroleptics (n = 277; RR = 0.88; 95% CI = 0.72 to 1.08)
Meiri et al,190 2007 DB, PC, RCT 5 Days 64 Day 1: N intensity on a VAS: dronabinol 10.1, ondansetron 24, combination 14.3,
• All patients received dexamethasone 20 and placebo 48.4. All active treatments significantly reduced intensity of N
mg, ondansetron 16 mg IV, dronabinol vs placebo (P < 0.05); no statistically significant differences between active
2.5 mg, and postchemotherapy groups observed
dronabinol 2.5 mg
Day 2:
• Dronabinol 10 mg/d, ondansetron
16 mg/d, or dronabinol 10 mg/d +
ondansetron 16 mg/d or placebo
Days 3 to 5:
• Dronabinol 10 to 20 mg/d, ondansetron
8 to 16 mg/d, or dronabinol 10 to 20
mg/d + ondansetron 8 to 16 mg/d or
placebo
Lane et al,192 1991 MC, DB, AC, Up to 6 days 62 • Dronabinol 10 mg Q6h + placebo No statistical difference in number of patients experiencing N after
RCT • Prochlorperazine 10 mg Q6h + placebo chemotherapy: dronabinol (47%), prochlorperazine (60%), combination
• Dronabinol + prochlorperazine therapy (29%)
Chan et al,193 1987d SC, DB, C, RCT NA 30 Single dose of nabilone or prochlorperazine • Significantly lower mean episodes of retching and V for nabilone vs
prior to chemotherapy, with the same prochlorperazine (13 vs 27, P < 0.05)
dose repeated 2 to 3 times daily • Significantly higher rate of improvement of retching and V with nabilone vs
prochlorperazine (70% vs 30%, P = 0.003)
(continued)
Dalzell et al,194 SC, DB, C, RCT 16 Months 18 • Nabilone PO 1 to 3 mg/d • Mean number of emesis episodes significantly lower with nabilone vs
1986d • Domperidone 15 to 45 mg/d domperidone (5 vs 16, P < 0.01)
• Mean severity of N was significantly milder with nabilone vs domperidone
(1 [mild] vs 2 [moderate], P = 0.01)
Niederle et al,195 SC, DB, C, RCT 2 Cycles of 20 Nabilone 2 mg bid vs alizapride 150 mg tid Reduction in frequency and severity of N during nabilone therapy compared
1986 chemotherapy with alizapride (P < 0.01)
Reduction in mean duration of N with nabilone compared with alizapride
(1.3 vs 5.1 h, P < 0.01)
Pomeroy et al,196 SC, DB, RCT; 1 Day 38 Nabilone 1 mg PO Q8h or domperidone Fewer episodes of V with nabilone compared with domperidone for cycle 1
1986 1-day duration 20 mg PO Q8h on day of chemotherapy (4.76 vs 12.95 (P < 0.02) and for cycles 1 and 2 combined (4.53 vs 10.81;
P < 0.01)
Niiranen and DB, C, RCT At least 2 32 • Nabilone 1 mg PO bid Lower mean number of emesis episodes with nabilone vs prochlorperazine
Mattson197 1985 cycles of • Prochlorperazine 7.5 mg PO bid (6.5 vs 11; P < 0.05)
chemotherapy
Ahmedzai et al,198 SC, DBDD, C, 3 Days 34 Nabilone 2 mg PO bid vs prochlorperazine Nabilone superior to prochlorperazine on day 1 for N (P = 0.005) and
1983 RCT PO 10 mg tid retching (P = 0.001), on day 2 for N (P < 0.01), retching (P > 0.01), and V
(P < 0.05), and on day 3 for anorexia (P < 0.05), N (P < 0.05), and V (P
< 0.001)
Johansson et al,199 DB, C, RCT NA 18 • Nabilone 4 mg PO daily • Nabilone associated with less N compared with prochlorperazine (1 vs 9,
1982 • Prochlorperazine 10 mg PO daily P = 0.027)
• Fewer mean number of V episodes (11.3 vs 23.7; P < 0.001), dry retching
(7.1 vs 15; P < 0.01), and overall N/V (18.4 vs 38.7; P < 0.001) with
nabilone vs prochlorperazine
Jones et al,200 1982 MC, DB, C, RCT NA 24 Nabilone 2 mg or placebo given evening Mean number of V episodes lower with nabilone vs placebo (7.2 vs 18.8;
before and morning of chemotherapy and P < 0.001)
Q24h thereafter Less N (65% vs 4%; P < 0.001) and V (79% vs 13%; P < 0.001) with
nabilone vs placebo
Levitt,201 1982d SC, DB, C, RCT NA 36 Nabilone or placebo More patients reported less V (4 vs 29; P < 0.001) and N with nabilone vs
placebo (2 vs 26; P < 0.001)
Einhorn,202 1982d SC, DB, C, RCT NA 80 Nabilone 2 mg Q6h prn vs Patients on nabilone reported 33% reduction of V on all days of
prochlorperazine 10 mg Q6h prn chemotherapy (P < 0.001)
Wada et al,203 1982 MC, DB, C, RCT 3 Days 104 Nabilone 2 mg PO vs placebo PO • Fewer emesis episodes occurred with nabilone vs placebo (4.19 vs 7.08; P
given evening before and morning of < 0.001)
chemotherapy and Q12h for 24 hours • Severity of N was significantly reduced with nabilone vs placebo (1.22 vs
afterward 1.96; P < 0.001)
Steele et al,204 1980 SC, DB, C, RCT Various 37 • Nabilone 2 mg PO Q12h Results varied based on emetic potential of the chemotherapy regimen; 18
• Prochlorperazine 10 mg PO Q12h (49%) patients achieved complete or partial elimination of N/V: 7 with
nabilone alone, 3 with prochlorperazine alone, and 8 with each drug
Herman et al,205 MC, DB, C, RCT NA 113 • Nabilone More patients responded to nabilone than prochlorperazine (80% vs 32%; P
1979 • Prochlorperazine < 0.001)
Duran et al,185 2010 MC, DB, RCT 4 Days 16 Nabiximols ≤8 sprays within any 4-hour Patients showing complete response significantly higher with nabiximols vs
period every 24 hours or placebo placebo (5/7 [71.4%] vs 2/9 [22.2%]; difference of 49.2%; 95% CI = 1% to
75%)
(continued)
11
12
Anderson et al,62 RCS Various 1120 Medical cannabis use associated with • Significant reductions of all program-reported symptoms when comparing
2019 cancer treatment: baseline scores with those submitted within the first 4 months of program
• 29% Used only high THC:CBD participation (P < 0.001 for all comparisons)
• 10% Used only balanced THC:CBD • Symptoms with ≥30% reduction in scores from baseline within 4 months:
• 1% Used only high CBD:THC anxiety (41.6%), lack of appetite (38.8%), depression (44.5%), disturbed
• 60% Used multiple products over the sleep (41.8%), fatigue (27%), N (40.5%), pain (30.0%), and V (49.8%)
study time
Enteral, inhaled, and oromucosal products
were reportedly used
Söderpalm et al,181 SC, DB, RCT NA 13 • Ondansetron and placebo cigarette Low-dose THC (P < 0.040), moderate-dose THC (P < 0.01), and
2001 • Placebo capsule and moderate-dose ondansetron (P < 0.001) significantly reduced N compared with placebo
marijuana cigarette (16.9 mg THC)
• Placebo capsule and low-dose marijuana
cigarette (8.4 mg THC)
• Placebo capsule and placebo cigarette
McCabe et al,191 SC, DB, C, RCT 1 Day 36 • THC 15 mg/m2 Q4h ×24 hours 23 Of 36 patients reported THC to be a superior antiemetic vs 1 for
1988 • Prochlorperazine 10 mg Q4h ×24 hours prochlorperazine (64% vs 3%)
Ungerleider et al,186 MC, DB, C, RCT 1 Day 214 • THC 7.5 mg for BSA <1.4 m2, 10 mg for • No significant difference in anti-N/antiemetic effect of THC compared
1982 BSA 1.4 to 1.8 m2, or 12.5 mg for BSA with prochlorperazine
>1.8 m2 PO Q4h ×4 doses • No difference between agents in food intake or appetite
• Prochlorperazine 10 mg PO Q4h ×4
doses
Chang et al,183 1981 SC, PC, C, RCT 1 Day 8 • THC 10 mg/m2 PO Q3h ×5 doses THC did not significantly reduce the number of V/retching episodes, volume
• Placebo of emesis, degree of N, or duration of N
THC cigarettes (smoked) given if patient
was actively V (900 mg weight, 1.93%
THC)
Orr et al,187 1980 DB, C, RCT 1 Day 55 THC 7 mg/m2 PO Q4h ×4 doses N was absent in 40 (73%), 8 (15%), and 5 (9%) patients receiving THC,
Prochlorperazine 7 mg/m2 PO Q4h ×4 prochlorperazine, or placebo (P = 0.05 for THC vs prochlorperazine and
doses P < 0.001 for THC vs placebo)
Placebo
Frytak et al,188 1979 PC, RCT 4 Days 116 • THC 15 mg PO tid Reduction in N/V on day 1 (most emetic influence) with THC vs placebo
• Prochlorperazine 10 mg PO tid ×3 days (P = 0.05) but no difference between THC and prochlorperazine; no
• Placebo capsules differences between any groups days 2 to 4 (P = 0.455)
Chang et al,184 1979d DB, C, RCT Various 15 • THC 10 mg/m2 BSA PO and/or smoked THC significantly reduced the number of episodes of N/V (P < 0.02),
cigarette (1.93%, ~17.4 mg THC degree of N (P < 0.01), duration of N (P < 0.01), and volume of emesis (P
• Placebo capsules and cigarettes < 0.01) compared with placebo
Sallan et al,189 1975 DB, RCT 3 Days 27 • THC PO 10 mg/m2 More patients reported a complete response of N with THC vs
• Prochlorperazine PO 10 mg prochlorperazine (40% vs 8%; P = 0.05)
(continued)
Pain (chronic noncancer, neuropathic)

Lynch and Ware210 MA 2 Weeks to 6 11 RCTs • Nabilone 0.5 to 1 mg/d (4 trials) 7 RCTs demonstrated that cannabinoids exhibited an analgesic effect
2015 months (n = 1185) • THC/CBD 2.7 mg/2.5 mg (nabiximols) significantly better than control
oromucosal spray (3 trials)
• Oral cannabis extract CBD 0.8 to 1.8 mg
and THC 2.5-mg capsule, max dose 25
mg THC (1 trial)
• Smoked cannabis, 4% THC (1 trial)
• Vaporized cannabis, 1.29% to 3.53% THC
(1 trial)
• FAAH inhibitor PF-04457845 (1 trial)
• Compared with placebo (9 trials) or
active control (2 trials)
Ware et al,214 2015 PCS 1 Year 431 • THC 12.5%: smoked, oral, and/or vaped Reduction in mean pain intensity score from baseline to 1 year was
cannabis (delivery system per patient observed in cannabis group (0.92; 95% CI = 0.62 to 1.23), but change was
preference) not significant in control group
• Patients not using cannabis
Issa et al,213 2014 SC, DB, RCT NA 30 • Dronabinol 10 mg Dronabinol 10- and 20-mg doses resulted in significant changes on 4 out of
• Dronabinol 20 mg 5 ARCI subscales compared with placebo (P < 0.05)
• Control group of patients without
chronic pain who smoked marijuana
cigarettes
Portenoy et al,70 MC, DB, RCT 5 Weeks 263 • Nabiximols oromucosal spray low dose 30% Responder rate primary analysis not significant for nabiximols vs
2012 (1-4 sprays/d), medium dose (6-10 placebo (P = 0.59)
sprays/d), and high doses (11-16 sprays/d)
• Placebo
Narang et al,225 2008 Phase 1: DB, C, 4 Weeks 30 Phase 1: Phase 1: total pain relief at 8 greater in those receiving dronabinol 20 mg
RCT • Dronabinol 10 mg vs placebo (sum of pain intensity difference: 41.7 vs 31.1, P < 0.01) and
Phase 2: OL • Dronabinol 20 mg dronabinol 10 mg compared with placebo (39.7 vs 31.1, P < 0.05)
• Placebo Phase II: statistically significant decrease in average pain scores from baseline
Phase II: (P < 0.001)
• Dronabinol 5 mg to 60 mg/d
Mücke et al,212 2018 MA 2 To 26 weeks 16 RCTs • THC/CBD 2.7 mg/2.5 mg (nabiximols) Cannabis-based interventions may increase the number of people achieving
(n = 1750) oromucosal spray (10 trials) 50% or greater pain relief compared with placebo (21% vs 17%; RD =
• Nabilone 0.25 to 4 mg (2 trials) 0.05; 95% CI = 0 to 0.09; P = 0.04; I2 = 29%). NNTB = 20 (95% CI =
• Inhaled herbal cannabis 1% to 9.4% THC 11 to 100)
(2 trials)
• Dronabinol 2.5 to 15 mg (2 trials)
Wilsey et al,217 2016 PC, RCT 3 Sessions 42 Inhaling either high-dose (6.7% THC), low- • Pain intensity (per 0 to 10 rating scale): both cannabis doses superior to
dose (2.9% THC), or placebo cannabis placebo at 120 minutes (P < 0.05); only higher dose retained significance
at 240 minutes (P < 0.01)
• Pain reduction by 30%: low- and high-dose arms were superior to
placebo (70% and 88% vs 45%, P = 0.0242, P < 0.0001, respectively). No
significant difference between low- and high-dose groups
(continued)
13
14
Hoggart et al,224 MC, OL, PCS 38 Weeks 234 THC/CBD 2.7 mg/2.5 mg (nabiximols) Neuropathic pain severity (0 to 10-point rating scale) decreased from 6.9 to
2015 oromucosal spray 4.2 from baseline in patients taking THC/CBD oromucosal spray
Wallace et al,222 DB, SC, C, RCT NA 16 • Low THC (1%) cannabis • Low-, medium-, and high-THC cannabis associated with significant
2015 • Medium THC (4%) cannabis decreases in spontaneous pain scores vs placebo
• High THC (7%) cannabis • Mean pain intensity score at the placebo dose was 0.44 points higher
• Placebo than low-dose cannabis (P = 0.031), 0.42 points higher than medium-
Study interventions provided as cigarettes dose cannabis (P = 0.04), and 1.2 points higher than high-dose cannabis
vaporized using the Volcano system (P < 0.001). Differences were also seen between high vs low and high vs
vaporizer medium cannabis doses (P < 0.001 for both comparisons)
Andreae et al,109 MA 6 Hours to 2 5 RCTs • Inhaled cannabis as prerolled cigarettes Inhaled cannabis resulted in short-term benefits for chronic neuropathic
2015 weeks (n = 178) 1% to 7% THC (3 trials) pain (NNT of 6)
• Inhaled via vaporizer (Volcano vaporizer)
8 to 12 puffs (10 to 28 mg THC per
session; 1 trial)
• Gelatin capsules 2.5% to 9.4% THC
(~5.85 mg/d; 1 trial)
Serpell et al,218 2014 MC, DB, PC, RCT 15 Weeks 246 • Nabiximols oromucosal spray • More patients receiving nabiximols vs placebo achieved ≥30%
• Placebo improvement in neuropathic pain score (28% vs 16%; OR = 1.97; P =
0.034); no difference in mean change from baseline (difference = −0.34; P
= 0.139)
• Significant improvements in sleep quality and PGIC were seen with THC/
CBD compared with placebo (P = 0.0072; P = 0.023)
Wilsey et al,216 2013 SC, C, RCT 3 Sessions 39 • Vaporized medium dose (3.53% THC), Pain intensity reduction by 30%: low- and medium-dose arms superior to
low dose (1.29% THC), or placebo placebo (57% vs 61% vs 26%; P = 0.0069; P = 0.0023); no significant
cannabis difference between low and medium cannabis groups (equianalgesic)
• 4 To 8 puffs of cannabis or placebo per
6-hour session, ×3 sessions separated by
3 to 14 days
GW PC, RCT 15 Weeks 297 • Nabiximols oromucosal spray No difference in number of patients with ≥30% improvement from baseline
Pharmaceuticals • Placebo between treatment and placebo (36% vs 40%; P = 0.521)
Ltd,223 2006
Wilsey et al,215 2008 SC, C, RCT 3 Sessions 38 High-dose THC cigarettes (7%) No significant change from baseline pain intensity between groups at 60,
Low-dose THC cigarettes (3.5%) 120, 180 minutes; lower pain intensity in cannabis groups at 240 minutes
Placebo cigarettes (P = 0.02)
Nurmikko et al,219 MC, PC, RCT 5 Weeks 125 • Nabiximols oromucosal spray Greater mean reduction in pain intensity (on a 0 to 10 scale) with
2007 • Placebo nabiximols vs placebo (−1.48 vs −0.52; P = 0.004)
Zajicek et al,166 2012 MC, DB, PC, RCT 12 Weeks 277 • Oral cannabis extract (THC/CBD 2.5 Proportion of patients with self-reported pain relief (categories 0 to 3 on
mg/0.8 to 1.8 mg) the CRS) significantly greater in the cannabis group vs placebo (29.4% vs
• Placebo 15.7%; OR = 2.26; 95% CI = 1.24 to 4.13; P = 0.004; 1-sided)
Skrabek et al,220 SC, DB RCT 8 Weeks 40 Nabilone 0.5-2 mg PO QHS Significant improvement with nabilone 2 mg/d from baseline to 4 weeks
2008 Placebo in VAS (−2.04; P < 0.02), FIQ (−12.07; P < 0.02), and FIQ anxiety scale
(−1.67; P < 0.02) vs placebo
(continued)
221
Blake et al, 2006 MC, DB, RCT 5 Weeks 58 • Nabiximols oromucosal spray • Improvement with cannabis vs placebo in morning pain on movement (MD
• Placebo = −0.95; P = 0.04), morning pain at rest (−1.04; P = 0.018), quality of
sleep (−1.17; P = 0.027), and DAS 28 (−0.76; P = 0.002)
• No differences in morning stiffness or SF-MPQ total intensity of pain
Haroutounian SC, OL, PCS 7 Months 176 Initial dose recommended was 20 g/month: Median S-TOPS pain symptom score in the cannabis group improved
et al,226 2016 smoked products or oral formulations from 83.3 to 75 (P < 0.001); pain symptom score improved in 65.9% of
patients, did not change from baseline in 8%, and deteriorated in 26.1% of
patients
Posttraumatic stress disorder (PTSD)
Elms et al,230 2019 OL, SC, RCS 8 Weeks 11 CBD PO capsule or PO liquid spray daily • After 4 weeks of CBD treatment, 10/11 (91%) patients reported a
or bid + standard psychiatric care and decrease in PTSD symptoms from baseline (from 51.8 ± 9 to 40.7 ± 13)
pharmacotherapy • At 8 weeks, 8/11 (73%) patients reported additional symptom decreases,
and 3 (27%) had worsening PTSD symptoms, though scores were still
lower than baseline scores
Greer et al,235 2014 RCS NR 80 Medical cannabis (dose, dosage form not CAPS total scores significantly reduced from baseline in patients treated
described) with cannabis (98.8 ± 17.6 to 22.5 ± 16.9; P < 0.0001); reduction was
also significant for cluster symptoms, re-experiencing, and hyperarousal
Roitman et al,236 PCS, OL, SC 3 Weeks 10 THC in olive oil 2.5-5 mg SL bid + current Decrease in symptom severity observed in PTSD hyperarousal symptoms,
2014 PTSD pharmacological regimen CGI-S, CGI-I, sleep quality, frequency of nightmares, and total NES scores;
no significant decrease in total CAPS score
Jetly et al,247 2015 DB, C, RCT 16 Weeks 10 • Nabilone PO 0.5-3 mg 1 hour before • Significant reduction in CAPS Recurring and Distressing Dream Scores
bedtime observed in nabilone group vs placebo (−3.6 ± vs −1 ± 2.1; P = 0.03)
• Placebo • 70% Rated improvement as “Very much improved” or “Much improved”
Cameron et al,248 SC, RCS 43 Months 104 Nabilone powder (removed from capsules) >97% Of patients reported increase in mean number of hours slept per
2014 and mixed in water night between pretreatment (5 ± 1.4) and posttreatment (7.2 ± 1.2) with
nabilone (P < 0.001)
~87% Of patients reported a decrease in the mean number of nights with
nightmares per week from pretreatment (5.2 ± 2.2) and posttreatment
(0.9 ± 1.8; P < 0.001)
Fraser,250 2009 PCS, OL, SC NR 47 Nabilone 0.5-6 mg PO 1 hour before 28 Patients (60%) experienced total cessation of nightmares, and 6 (13%)
bedtime + current psychotropic regimen more had satisfactory lessening of severity of nightmares
Terminal illness and hospice care
Mücke et al,67 2018 MA Variable 9 Studies • Dronabinol (6 studies) • Cancer patients: no significant difference between cannabinoids and
(n = 1561) • Combination of THC/CBD (3 studies) placebo for improving caloric intake (MD = 0.2; 95% CI = −0.66 to 1.06;
• C sativa (1 study) P = 0.65), appetite (MD = 0.81; 95% CI = −1.14 to 2.75; P = 0.42), N/V
(MD = 0.21; 95% CI = −0.10 to 0.52; P = 0.19), >30% decrease in pain
(RD = 0.07; 95% CI = −0.01 to 0.16; P = 0.07), or sleep problems (MD
= −0.09; 95% CI = −0.62 to 0.43; P = 0.72)
• HIV patients: cannabinoids superior to placebo for weight gain (MD =
0.57; 95% CI = 0.22 to 0.92; P = 0.001) and appetite (MD = 0.57; 95% CI
= 0.11 to 1.03; P = 0.02) but not N/V (MD = 0.20; 95% CI = −0.15 to
0.54; P = 0.26)
Kuhlen et al,267 2016 R, O 23 To 1429 days 16 Dronabinol 2.5% oily solution 0.08 to 1 12 Of 16 patients reduced spasticity with dronabinol; therapeutic effect
mg/kg/d PO bid could not be determined in 2 patients, and dronabinol was ineffective in 2
patients (no statistics provided)
15
(continued)
16
75
Bar-Sela et al, 2013 P, O 6 To 8 weeks 211 Cannabis dosage forms used: smoking, Significant improvement in all cancer- or chemotherapy-related symptoms,
inhalation, or oil including N, V, mood disorders, fatigue, weight loss, anorexia,
constipation, sexual function, sleep disorders, itching, and pain after taking
cannabis for 6 to 8 weeks (P < 0.001)
Portenoy et al,70 DB, PC, RCT 9 Weeks 360 • Low-dose nabiximols • No significant difference between nabiximols groups and placebo in 30%
2012 • Medium-dose nabiximols reduction in baseline pain (P = 0.59)
• High-dose nabiximols Placebo • Significant improvement in sleep disruption NRS (OR = −0.88; P < 0.003)
with low-dose nabiximols vs placebo
Brisbois et al,57 2011 DB, PC, RCT 18 Days 46 • Dronabinol 2.5 mg PO bid • No difference in mean taste and smell perception survey scores between
• Placebo PO bid dronabinol (5.7) and placebo group (6.4); P = 0.225
• Majority (73%) of dronabinol patients reported increased overall
appreciation of food vs placebo (30%) and more often stated that
dronabinol “made food taste better” (55%) vs placebo (10%; P = 0.04)
• No difference in mean total caloric intake with dronabinol (1726 Kcal/d)
vs placebo (1647 Kcal/d); P = 0.425
Johnson et al,71 2010 MC, DB, PC, RCT 14 Days 177 • Nabiximols spray • Reduction in mean pain score with nabiximols spray (0.67; P = 0.014) vs
• THC spray placebo
• Placebo spray • No reduction in mean pain score with THC extract (0.32 points; P =
0.245) vs placebo
Cannabis-In- MC, DB, PC, RCT 6 Weeks 243 • Cannabinoid extract (2.5 mg THC and 1 • No significant difference among CE, THC, or placebo groups regarding
Cachexia-Study- mg CBD per capsule) PO bid mean (±SD) appetite improvement (5.4 ± 24.7 mm, 18.5 mm [no SD
Group et al,60 • THC 2.5-mg capsule PO bid given], or 5.8 ± 23.8 mm, respectively; P = 0.46) or mean overall QOL
2006 • Placebo capsule PO bid (1.1 ± 19.2, 5.1 ± 21.2, and 3 ± 19.5)
•
Jatoi et al,56 2002 DB, MC, RCT 57 To 80 days 485 • MAc group: MAc suspension 800 mg PO • Significantly more patients receiving MAc (75%) reported increased
daily + placebo PO bid appetite vs dronabinol (49%); P = 0.0001
• Dronabinol group: dronabinol 2.5 mg PO • No significant difference between patients receiving MAc (75%) or
bid + placebo PO daily MAc+D (66%) in improvement in appetite; P = 0.17
• MAc+D group: MAc suspension 800 mg • Significantly more patients receiving MAc (11%) experienced ≥10% weight
PO daily + dronabinol 2.5 mg PO bid gain from baseline vs dronabinol (3%); P = 0.02
• No significant difference between patients receiving MA (11%) or MA+D
(8%%) in experiencing ≥10% weight gain from baseline; P = 0.43
Abbreviations: AC, active control; AE, adverse event; AED, antiepileptic drug; APSI, Autism Parenting Stress Index; ARCI, Addiction Research Center Inventory; ART, antiretroviral therapy; BMI, body mass index; BSA,
body surface area; C, crossover; CAPS, Clinician Administered Posttraumatic Scale; CBD, cannabidiol; CCGIC, Caregiver Clinical Global Impression of Change; CD, Crohn disease; CDAI, Crohn Disease Activity Index; CE,
cannabinoid extract; CGI, Clinical Global Impression; CGI-I, Clinical Global Impression Scale, global improvement; CGI-S, Clinical Global Impression Scale, severity of illness; CMAI, Cohen-Mansfield Agitation Inventory; CRI,
credible interval; CRS, Category Rating Scale; D, dronabinol; DAI, Disease Activity Index; DAS 28, 28 Joint Disease Activity Score; DB, double bind; DBDD, double blind, double dummy; FAAH, fatty acid amide hydrolase;
FIQ, Fibromyalgia Impact Questionnaire; GAF, Global Assessment of Functioning; HBI, Harvey-Bradshaw Index; HCV, hepatitis C virus; HRQoL, health-related quality of life; IQR, interquartile range; ITT, intention to treat; IV,
intravenous; MA, meta-analysis; MAc, megestrol acetate; MAS, Modified Ashworth Scale; max, maximum; MC, multicenter; MD, mean difference; N, nausea; NA, not applicable; NES, Nightmare Effects Survey; NNT, number
needed to treat; NNTB, NNT to benefit; NPCRA, nonparametric circadian rhythm analysis; NPI, Neuropsychiatric Inventory; NR, not reported; NRS, Numeric Rating Scale; NRS-PI, Numeric Rating Scale for pain intensity; O,
observational; OCE, oral cannabis extract; OL, open label; OR, odds ratio; P, prospective; PAS, Pittsburg Agitation Scale; PC, placebo controlled; PCS, prospective cohort study; PD, prospective descriptive trial; PGIC, Patient
Global Impression of Change; PO, by mouth; PP, per protocol; QHS, every night at bedtime; QOL, quality of life; R, retrospective; RCS, retrospective cohort study; RCT, randomized controlled trial; RD, risk difference; RMI,
Rivermead Mobility Index; RR, relative risk; SA, single arm; SB, single blind; SC, single center; SF-MPQ, Short-Form McGill Pain Questionnaire; SL, sublingual; SLIM, Satiety Labeled Institute Magnitude; SMD, standardized mean
difference; S-TOPS, treatment outcomes in pain survey short form; THC, tetrahydrocannabinol; UC, ulcerative colitis; UCAI, Ulcerative Colitis Activity Index; V, vomiting; VAS, Visual Analog Scale.
a
MA and SR reporting on multiple disease states, case studies, and surveys not included in the table.
b
There was a lack of enrollment because the condition of interest (ie, nighttime agitation) was associated with significant cognitive decline and precluded most patients from providing informed consent; accordingly, no statistical
analyses were conducted.
c
Outcome was adjusted for age, disease duration, gender, spasticity duration, and value at baseline.
d
Pediatric patients were included in the study.
e
Clinical remission was defined as a Mayo score <2.
Inglet et al 17
Table 2. Dosage Forms and Strengths Evaluated in the Literature, by Disease State.
Route Dosage forms and strengths
Alzheimer disease
Oral Dronabinol capsule: 2.5 mg
• Dose range: 2.5 mg once daily to bid
Nabilone capsule: NR
• Dose range
○ 0.5 mg Once daily to bid
○ 1 To 2 mg daily (mean reported dose: 1.6 mg)
○ Oil: 1.65% THC, 0.05% CBD
• Dose range (THC): 2.5 to 7.5 mg bid
THC tablet: 0.75 mg, 1.5 mg
• Dose range
○ 0.75 To 1.5 mg bid
○ 1.5 mg tid
Amyotrophic lateral sclerosis
Oral Dronabinol oil: 2.5 mg THC per 3 drops
• PK study dose: 5 mg once, 10 mg once
• RCT dose: 5 mg bid
Nabiximols oromucosal spray: 2.7 mg THC, 2.5 mg CBD per 100-µL actuation
• Dose range: NR
○ Mean clinical trial dose: 6.1 to 8.03 actuations (1.6-2.2 mg THC, 1.5-2 mg CBD) daily
○ Case report dose: 3 mL (81 mg THC, 75 mg CBD) daily
Autism spectrum disorder
Oral Oil, sublingual or ingested: CBD:THC ratio 20:1
• Dose range (CBD):
○ 90 mg/d (IQR, 45 to 143 mg/d)
○ 238.5 ± 184.5 mg/d Divided tid
• Dose range (THC):
○ 7 mg/d (IQR, 4 to 11 mg/d)
○ 12 ± 9 mg/d Divided tid
Oil, sublingual or ingested: CBD:THC ratio < 6:1
• Dose range (CBD):
○ 3.8 ± 2.6 mg/kg/d Divided tid
○ 1.8 ± 1.6 mg/kg/d Divided bid
• Dose range (THC):
○ 0.29 ± 0.22 mg/kg/d Divided tid
○ 0.22 ± 0.14 mg/kg/d Divided bid
Cancer
Oral Oral capsule: Dronabinol (Marinol, Syndros; semisynthetic THC)
• Dose ranges from 2.5 to 20 mg/d
Oral capsule: THC (cannabis extract)
• Dose 2.5 mg bid
Oral capsule: THC and CBD
• Dose THC-CBD 2.5 to 1 mg bid
Enteral THC
• Dose and strength not specified
Oromucosal nabiximols (Sativex)
• Dose THC-CBD 2.7-2.5 mg per actuation (100 µL) with daily titrations if needed
Oromucosal THC
Oral capsule: Nabilone (synthetic THC)
• Dose ranges from 0.5 to 2 mg/d
Inhaled Inhaled/vaporized cannabis
Dabbing/ THC aliquot delivered via infusion catheter into tumor resection cavity
Other
Epilepsy and seizures
(continued)

Oral Oral solution: cannabidiol (Epidiolex) 100 mg/mL

• Dose range: 5 to 20 mg/kg/d divided bid
Oil, sublingual: CBD:THC ratio 20:1
• Dose IQR (CBD): 2.9 to 7.5 mg/kg/d divided bid or tid
Oil, sublingual or ingested: CBD:THC ratios ranging from 15:1 to 27:1
• Dose range (CBD): 1 to 9 mg/kg/d
Oil, sublingual or ingested: CBD with <0.1% or <0.3% THC
• Dose range (CBD): 1 to 3.9 mg/kg/d
Inhaled Vaping: dried cannabis flower buds (concentration/strain not described)
• Dose administered via Volcano Medic Vaporizer, PUFFiT, or inhaler device
Smoking: dried cannabis flower buds (concentration/strain not described)
• Dose and technique not described
HIV and AIDS
Inhaled Inhaled or smoked:
• Dose range (THC): 1% to 8%, 3.56%, 3.95%
Inflammatory bowel disease
Oral Capsule: 50 mg CBD-rich extract with ≤4.7% THC
• Dose range (CBD): 50 to 250 mg bid
Oil, sublingual: 5 mg/mL CBD (99.5% purity)
• Dose (CBD): 10 mg bid
Oil: 15% CBD, 4% THC
• Dose: NR
Inhaled Smoking: 11.5 mg THC in 500 mg cannabis, CBD content NR
• Dose (THC): 23 mg daily
Smoking: 115 mg THC in 500 mg cannabis, CBD < 0.5%
• Dose (THC): 115 mg bid
Multiple sclerosis
Inhaled Smoking: 4% THC
• Dose: 1 cigarette daily ×3 days
Oral Capsule: THC 2.5 mg:CBD range 0.8 to 1.8 mg
• Dose (THC): 53% taking 10 or 15 mg daily; 47% taking 25 mg daily = maximum dose
Capsule: THC 2.5 mg:CBD 0.9 mg
• Dose (THC): 14.5 ± 8.7 mg daily to 20.0 ± 9 mg daily; maximum 30 mg daily
Capsule: THC 2.5 mg:CBD 1.25 mg
• Dose: 2.34 to 7.99 capsules daily
Capsule: THC 2.5 mg as dronabinol (Marinol)
• Dose: 5 mg daily to 35 mg daily; maximum dose varied between studies
Oromucosal spray: THC 2.7 mg:CBD 2.5 mg per 100-µL actuation as nabiximols (Sativex)
• Dose: mean THC >25 mg daily (or 8.91 actuations to 15 actuations daily); maximum dose ranged from 24
sprays in 24 hours to 8 sprays in 3 hours
Oromucosal spray: THC 2.5 mg:CBD 2.5 mg per actuation
• Dose range (THC): 2.5 to 120 mg daily; mean 33.7 mg daily
Oromucosal spray: THC 2.5 mg per actuation
• Dose range (THC): 2.5 to 75 mg daily; mean 31.2 mg daily
Rectal Suppository: 2.5 to 5 mg
• Dose: 5 mg daily ×4 days
Nausea and vomiting
Oral Oral capsule: dronabinol (semisynthetic THC)
• Dose range 10 to 20 mg per dose tid to qid
• Or 7 to 10 mg/m2 every 3 hours on chemotherapy days
• Most common 15 mg tid up to qid
Oral capsule: nabilone (synthetic THC)
• Dose range 1 to 2 mg bid to qid
Oromucosal spray: nabiximols (2.7 mg THC/2.5 mg CBD)
• Dose range up to 8 sprays within 4 hours of chemotherapy
Oral cannabis extract:
• THC 2.5 mg and CBD 2.5 mg tid
Oral THC: various
• Dosage range 7 to 15 mg/m2 per BSA tid to 5 doses within 4 hours of chemotherapy
(continued)
Inglet et al 19

Inhaled Smoking: dried cannabis flower buds in cigarettes

• THC 8.4 to 17.4 mg
Inhaled within 4 hours of chemotherapy
Pain
Oral Oral capsule: nabilone (synthetic THC)
• Dose ranges 0.25 to 4 mg/d
Oral capsule: dronabinol (semisynthetic THC)
• Dose ranges 5 to 60 mg/d
Oromucosal spray: nabiximols (THC/CBD, 2.7 mg/2.5 mg per actuation)
• Dose ranges up to 24 sprays/d (64.8 mg THC/60 mg CBD)
Oral cannabis extract: THC 2.5 to >100 mg and CBD 0.8 to 55 mg
• Highly variable
• Dose ranges often include maximum dose of 25 mg THC
Oral THC: various
• Dosage ranges 5 to 60 mg/d
Inhaled Vaping: dried cannabis flower buds or oil (1.29% to 12.5% THC)
• THC:CBD is variable (often 15:1)
• Dose administered via Volcano Medic Vaporizer or inhaler device
• Dose ranges variable, often up to 12 puffs per session
Smoking: dried cannabis flower buds or gelatin capsules (1% to 14% THC)
• THC:CBD variable (often 15:1)
• Cigarettes, pipe, or other techniques not described
• Dose range variable, often up to 12 puffs per session
Posttraumatic stress disorder
Oral Capsule: 25 mg CBD (<0.3% THC) PO daily or bid
Sublingual spray: 25 mg CBD (as oil) SL QHS, plus 6 to 12 mg SL prn daytime anxiety
Sublingual spray: 1.5 mg CBD per spray SL daily or bid
Sublingual oil: 100 mg THC dissolved in 4 mL olive oil
• Dosed as 2.5 mg (0.1 mL) SL bid
• If tolerated, may increase to 5 mg (0.2 mL) SL bid
Inhaled Smoking: unprocessed cannabis flower buds with 23% THC and <1% CBD
Smoking: resin, THC and CBD in a 1:1 ratio
Terminal illness and hospice care
Oral Dronabinol oral solution: 2.5%
• Dose range: 0.08 to 1 mg/kg/d (1.7 to 15.1 mg/d)
Dronabinol capsule: 2.5 mg
• Dose range: 5 to 20 mg/d
Oral capsule: THC 2.5 mg/CBD 1 mg
• Daily dose: THC 5 mg/CBD 2 mg
Oral capsule: 2.5 mg THC
• Daily dose: 5 mg
THC/CBD spray: 2.7 mg THC and 2.5 mg CBD/actuation
• Dose range: 1 to 16 sprays/d
THC spray: 2.7 mg THC
• Dose range: 1 to 16 sprays/d
Inhaled Smoking: THC/CBD concentration ranged from 16% to 27% and 0.5% to 2%, respectively
• Dose range not specified
Inhalation: THC/CBD concentration ranged from 16% to 27% and 0.5% to 2%, respectively
Topical Oil: THC/CBD concentration ranged from 16% to 27% and 0.5% to 2%, respectively15
Abbreviations: BSA, body surface area; CBD, cannabidiol; IQR, interquartile range; NR, not reported; PK, pharmacokinetic; RCT, randomized
controlled trial; SL, sublingual; THC, tetrahydrocannabinol.
may be associated with euphoria, confusion, and somno- especially at higher doses.18 No current clinical practice
lence.16,25 Cannabis-based products could also increase the guidelines were identified that discuss the use of medical
risk for falls secondary to changes in balance and gait, cannabis in AD.28-33
Amyotrophic Lateral Sclerosis Commonly reported adverse events of cannabis-based

products in patients with ASD included appetite and energy-
Clinical efficacy data for medical cannabis use in amyo- level changes, irritability, and somnolence.42-45 No current
trophic lateral sclerosis (ALS) are conflicting. Small placebo- clinical practice guidelines recommend the use of medical
controlled crossover studies and a case report did not find cannabis in ASD.54,55 The American Academy of Pediatrics
medical cannabis effective for the management of muscle (AAP) published a policy statement advocating against
spasticity in patients with ALS.34-36 On the other hand, the medical cannabis for children. Reasons included were, first,
Cannabis sativa Extract in Amyotrophic Lateral Sclerosis medical cannabis is not regulated by the FDA; second, the
and other Motor Neuron Disease (CANALS) study was iden- purity of CBD and THC content are not consistently veri-
tified as the most recent and highest-quality trial in terms of fied and cannot be guaranteed; and third, the risk-benefit
study design and size, investigating nabiximols in patients relationship cannot be determined because of the lack of
with ALS.37 Patients receiving nabiximols oromucosal spray robust clinical data. For children who have life-limiting or
experienced decreased muscle spasticity (−0.32; 95% CI = severely debilitating conditions and for whom current ther-
−0.57 to −0.069), measured with the Modified Ashworth apies are inadequate, the AAP recognized that medical can-
Scale, and reduced pain (−1.15; 95% CI = −2.1 to −0.21), nabis may be an option.55
measured with the Numeric Rating Scale, compared with
patients receiving placebo.37 Patients receiving nabiximols
were also more likely to note clinical improvement compared Cancer
with patients receiving placebo (55% vs 13%; P = 0.001).37 Cachexia. Limited patient-reported data suggest that medi-
Safety data on medical cannabis use in ALS patients are cal cannabis may offer a benefit in cancer-related
limited by low patient enrollment and short duration of cachexia.56-62 To date, no available clinical trials demon-
treatment.34,36-38 Common potentially treatment-related strated a benefit on body weight, caloric intake, quality of
adverse effects from cannabis-based medications included life, or appetite when compared with placebo or meges-
asthenia, disorientation, dizziness, dry mouth, nausea, para- trol.56-61 A large retrospective study showed significant
doxical muscle spasticity or rigidity, somnolence, and ver- improvements in appetite for those using medical cannabis
tigo.37 Serious adverse event rates among ALS patients (≥30% improvement within 4 months), but outcomes were
were low, when reported.34,37 No current clinical practice patient reported, dosage and THC to CBD ratios varied, and
guidelines were identified that discuss the use of medical there was no comparator cohort.62
cannabis in ALS.39-41
Treatment of Cancer. The antitumor activity of cannabinoids
was evaluated in a single phase I clinical trial of 9 patients
Autism Spectrum Disorder with glioblastoma multiforme who had failed standard ther-
In preclinical and clinical data, CBD oil with minimal THC apy.63 Each patient received an aliquot of THC solution via
has not demonstrated consistent efficacy and safety as mono- catheter into the resection cavity for a range of 1 to 6 cycles
therapy or add-on treatment in pediatric patients with autism (total THC dose received ranged from 0.80 to 3.29 mg).
spectrum disorder (ASD).42-45 Additionally, some evidence is Median survival from the surgical operation of tumor
indirectly based on the efficacy of CBD in pathological condi- relapse was 24 weeks and 2 patients survived 1 year.63
tions (eg, attention-deficit hyperactivity disorder) that could Additionally, 2 case reports describe a correlation between
also present in ASD.42-44,46-48 The effects of CBD with or with- inhaled cannabis and cannabis extract and remission of
out THC and dronabinol were evaluated on tangential symp- acute lymphoblastic leukemia and astrocytoma.64,65
toms or comorbidities associated with ASD (eg, irritability,
aggressive behavior, sleep disorders) and not the core symp- Cancer-Related Pain. The preponderance of evidence does
toms of ASD (eg, persistent deficits in social communication not show a significant beneficial treatment effect for medi-
and interaction, nonverbal behaviors, and sensory reactiv- cal cannabis in cancer-related pain.66-72 A meta-analysis of 4
ity).42-45,49 In cohort studies of ASD patients given CBD oil, randomized controlled trials of cancer patients (n = 1539)
caregivers reported 40% to 70% improvements in anxiety, found no significant difference in the proportion of patients
hyperactivity, mood, rage attacks, restlessness, and self-injury. who achieved at least 50% pain reduction with medical can-
These improvements were not significantly different between nabis (including cannabis-based medications) compared
CBD oil and conventional treatments such as antipsychotics, with placebo (11.8% vs 9.7%, P = 0.82). Additionally, more
antidepressants, and behavioral and educational coaching.42-45 patients receiving medical cannabis withdrew from the
Randomized controlled trials of medical cannabis in ASD studies as a result of adverse events (P = 0.03).66 A second
patients are underway, including an open-label dose-discov- meta-analysis included 8 studies in patients with end-stage
ery trial, a randomized, controlled phase II trial, and 2 other medical diseases, including cancer, dementia, HIV/AIDS,
trials investigating cannabidivarin.50-53 heart disease, lung disease, and liver disease, and found no
Inglet et al 21
difference in the proportion of patients who achieved ≥30% and appetite changes.77-99 Cannabidiol oral solution
pain reduction with medical cannabis compared with pla- (Epidiolex), specifically, was also associated with diarrhea
cebo (30.5% vs 22.7%; P = 0.07).67 (because of its formulation in sesame oil) and an increase in
Although a limited number of small clinical trials of liver function tests.78-88
nabilone and nabiximols did demonstrate significant bene- No current clinical practice guidelines recommend the use
fits over placebo for pain relief,61,73-75 these results are gen- of medical cannabis in epilepsy or seizure disorders.100-102 In
erally outweighed by larger trials showing no significant their respective position statements, the American Epilepsy
benefit from medical cannabis in general.68-72 Society and the AAP emphasize the lack of robust clinical
Across all trials in cancer patients, commonly reported trial data and also urge caution with non-FDA-approved can-
adverse events were nausea and vomiting, dizziness, som- nabis products because of the inability to guarantee concen-
nolence, dry mouth, and headache.56-63,66-75 The National tration or purity of the products.55,103
Comprehensive Cancer Network Palliative Guidelines state
that data to support the use of medical cannabis in cancer/ Human Immunodeficiency Virus (HIV) and
cachexia are limited, citing trials that failed to demonstrate
Acquired Immune Deficiency Syndrome (AIDS)
the benefit of cannabis products or dronabinol over placebo
or megestrol acetate.76 The guidelines do mention that med- The use of medical cannabis in patients with HIV or devel-
ical cannabis may be helpful for some patients with cancer- oped AIDS is intended to manage disease-related symptoms
related cachexia but caution against use in the elderly (eg, anorexia, cachexia, nausea/vomiting, neuropathic pain)
population because these patients may be more susceptible or adverse effects of antiretroviral therapy.15,104-116
to delirium.76 Currently, there are no guidelines that recog- Dronabinol is FDA approved for the treatment of HIV-
nize the use of medical cannabis as treatment for cancer or associated wasting syndrome based on a phase III clinical
treatment of cancer-related pain. trial, which found significant improvement in appetite and
nonsignificant improvement in weight, mood, and nausea in
patients treated with dronabinol compared with placebo.6-9
Epilepsy and Seizure Disorders The most robust evidence for other medical cannabis prod-
The available body of literature suggests that CBD, in addi- ucts is described for the treatment of HIV-associated sen-
tion to a prescription antiepileptic drug regimen, may sory neuropathy (HIV-SN).108-111 Two randomized,
reduce seizure frequency in patients with refractory epi- placebo-controlled trials found that 28% of patients with
lepsy and other severe seizure disorders.77-99 Depending on HIV-SN achieved clinically and statistically significant
the product, formulation, and concentration evaluated in the reductions in pain (≥30% from baseline) with smoked can-
study, between 33% and 70% of patients achieved ≥50% nabis products, with a number needed to treat (NNT) of
reduction in seizures from baseline, though this end point is 4.108-110 Evidence for medical cannabis on viral suppression
subjectively reported.77-99 The only randomized controlled is inconsistent and limited to low-quality studies,117-122 and
trials identified describe cannabidiol oral solution reports on disease progression, medication adherence, and
(Epidiolex).78-81 A meta-analysis of these trials found that quality of life are conflicting.106,120,123-135
the pooled MD in seizure frequency between cannabidiol Preliminary evidence indicates that medical cannabis
10 and 20 mg/kg/d compared with placebo was statistically use may independently and synergistically accelerate neu-
significant (19.5% and 19.9%; P = 0.001 and P < 0.001 rocognitive impairment in HIV patients already experienc-
respectively).77 A 50% reduction in all seizure types ing memory deterioration.136,137 Smoked cannabis products
occurred in 37.2% of patients receiving 20 mg/kg/d and may be a burden on the lungs and introduce a pathway for
21.2% of patients receiving placebo, which was statistically pathogens to the lungs.112 In patients with HIV and hepatitis
significant, but demonstrates the high placebo effect associ- C virus coinfection, medical cannabis use decreased the
ated with subjectively reported outcomes.77 prevalence of steatosis but did not affect the prevalence or
Observational studies describing cannabidiol oral solution progression of hepatic fibrosis.131-134 Other commonly
(Epidiolex) and CBD oils with or without THC as well as very reported adverse effects include sedation, confusion and
limited data describing vaporization or smoking of dried can- inability to concentrate, and dry mouth.108-111,117 No current
nabis flower buds have also reported cannabis as “successful” clinical practice guidelines recommend the use of medical
in reducing seizures in as many as 71% of children and 89.5% cannabis in HIV.138,139
of adults with epilepsy.82-99 In these studies, the dosage, for-
mulations, and patient populations vary widely.82-99
In several studies, a small subset of patients (5% to 18%)
Inflammatory Bowel Disease
unpredictably experienced an increase in seizure frequency Evidence for medical cannabis use in inflammatory bowel
on initiating medical cannabis treatment.83,95-97 Commonly disease (IBD) such as Crohn disease (CD) and ulcerative
reported adverse events include somnolence, irritability, colitis (UC) is conflicting and limited to trials with small
sample sizes that enrolled patients who failed conventional the largest randomized controlled trial identified, and it stud-
therapies (eg, 5-aminosalicylic acid derivatives, anti–tumor ied spasticity in 630 MS patients. The study found no differ-
necrosis factor therapies, azathioprine, corticosteroids, mer- ences in the Ashworth Spasticity Scale between either oral
captopurine, methotrexate).140-149 In 1 study, clinical cannabis extract (THC 2.5 mg:CBD 1.25 mg) or THC (2.5
response rates were significantly higher in CD patients mg) compared with placebo after 15 weeks. The patient-
smoking cannabis cigarettes compared with placebo ciga- reported secondary end points evaluating pain reduction,
rettes (relative risk [RR] = 2.27; 95% CI = 1.04 to 4.97).142 muscle spasms, and sleep quality were significant, favoring
Conversely, multiple randomized controlled trials showed the experimental groups.171 In a 12-month follow-up study
no difference in clinical remission rates among IBD patients of the CAMS study population, in which only a small pro-
receiving cannabis-based products compared with IBD portion continued receiving blinded treatment, spasticity
patients receiving placebo, regardless of product formula- scores were significantly improved in the cannabis extract
tion.140,141,143,146,147,149 No data were identified for the use of and THC groups compared with the placebo group (1.82 vs
medical cannabis in quiescent CD or UC. 0.10 vs −0.23, respectively; P = 0.04).172
Short-term medical cannabis use for IBD was associated Long-term safety data are lacking for medical cannabis
with significantly more adverse effects compared with pla- use in MS. There is an association of increased suicide
cebo—most commonly, dizziness, nausea, and somno- risk101,176 and cognitive impairment101 in patients with MS,
lence.142,146,147,149 In 1 study reporting withdrawal rates, and some evidence suggests that cannabis-based products
more patients receiving cannabis-based products withdrew can also increase suicide risk101 and cognitive impair-
as a result of adverse effects compared with placebo (38% ment,101,163 hence raising concern for putting MS patients at
vs 6%).141 No data were identified describing the long-term compounded risk. The most commonly reported adverse
safety of medical cannabis exposure in IBD patients. effects reported in trials were fatigue, weakness, nausea,
No current clinical practice guidelines discuss the use of and dizziness, though in some trials, rates were similar in
medical cannabis in adults with IBD.149-155 The 2018 the placebo groups.159,168,169,171,174,175
European Crohn’s and Colitis Organization (ECCO) and The 2019 Association of British Neurologists guidelines
European Society of Paediatric Gastroenterology, recommend medical cannabis only for refractory MS patients
Hepatology and Nutrition (ESPGHAN) guideline for the who have not responded to conventional spasticity drugs,
management of acute severe pediatric UC recommends stating that evidence from clinical trials for spasticity are
against the use of medical cannabis for acute pain because inconsistent.179 The 2019 National Institute for Health and
there are no data to support use and because of a theoretical, Care Excellence guidelines on medical cannabis use state
detrimental risk of diminished peristalsis.156 The 2018 that providers may consider a 4-week trial of THC:CBD
ECCO/ESPGHAN guideline for the management of UC in spray to treat moderate to severe spasticity secondary to MS
the ambulatory setting comments on the lack of evidence to if other treatments for spasticity have been tried and are not
support use of alternative medicines, including medical effective and payment is accounted for.180 The National
cannabis, in pediatric IBD.157 Multiple Sclerosis Society supports the rights of people with
MS to work with their MS health care providers to access
medical cannabis in accordance with legal regulations in
Multiple Sclerosis and Spasticity those states where such use has been approved.62
Medical cannabis has been studied for the treatment of a
number of multiple sclerosis (MS) symptoms, including
Nausea and Vomiting
bladder dysfunction or lower urinary tract symptoms,158-160
central neuropathic pain,161-163 and muscle spasms or spas- The bulk of clinical data are focused on chemotherapy-
ticity,164-175 with spasticity having the most evidence. The induced nausea and vomiting (CINV) and feature a variety
majority of data suggest that medical cannabis has benefi- of medical cannabis doses and formulations, including
cial effects in the treatment of MS-related symp- smoked cannabis cigarettes,181-185 THC oils,184-190 and can-
toms.159,160,162-170,172,176-178 The positive outcomes are nabis-based medications nabiximols,191 dronabinol,192,193
specific to pharmaceutical cannabis-based medications and nabilone.194-206 Overall, evidence for medical cannabis
such as nabiximols (Sativex) oromucosal spray, which dem- use in nausea and vomiting suggests benefit over pla-
onstrated benefit in the treatment of MS-related spasticity cebo182,185,189,191,201,202,204 and equivalence to some conven-
and neuropathic pain in multiple clinical tri- tional antiemetics,186,190,194-200,203,205,206 with a NNT as low
als.160,161,163-166,168-170,175 Of note, medical cannabis has lim- as 4 patients treated with cannabis for 1 patient to achieve
ited evidence of neuroprotective action171 and no evidence complete control of CINV.207 Most trials with active com-
of disease-modifying efficacy.176 parators featured prochlorperazine, and only a few small
The Cannabinoids for Treatment of Spasticity and Other studies compared cannabis with a serotonin (5-HT3) recep-
Symptoms Related to Multiple Sclerosis (CAMS) study was tor antagonist.182,192
Inglet et al 23
Dronabinol is FDA approved for adults with CINV and that higher doses may not produce improved analgesia but
has been shown to be as effective as conventional therapies do cause more adverse effects.70,216-218,223,226 Some studies
and superior to placebo in the treatment of CINV.6-10,192,193 included concurrent use of opioids and did not report
Nabilone is also FDA approved for adults with CINV6-8,11; it increased adverse events compared with studies not includ-
has been shown to be superior to placebo and active-comparing concurrent opioids.219,227
ator antiemetics, including in 2 studies in pediatric patients, Current clinical practice guidelines do not comment on
but often causes more adverse effects.194-206 Nabiximols was the use of medical cannabis for pain. The American Pain
evaluated in only 1 small randomized controlled trial (n = Society published a position paper preparing clinicians to
16) for CINV, in which it demonstrated improvement over care for patients who use it and identified directions for
placebo (71.4% vs 22.2%; 95% CI = 1 to 75).191 research.228 The International Association for the Study of
Evidence generally suggests increased adverse effects Pain has identified members for a Task Force on Cannabis
from medical cannabis compared with placebo and anti- and Cannabinoids.229 The European Pain Federation pub-
emetic agents.15,183,207,208 The most common adverse effects lished a position paper on the appropriate use of medical
include dizziness, dysphoria, euphoria, feeling high, and cannabis stating that nabiximols may be considered in
sedation.15,183,207,208 Despite increased adverse events, many patients whose cancer pain is unrelieved from opioids or
studies found that patients may prefer medical cannabis other established analgesics and that medical cannabis
over other agents.15,194,195,200,203 products may be considered third-line therapy for chronic
The American Society of Clinical Oncology 2017 guide- neuropathic pain.230
lines state that evidence remains insufficient for a recom-
mendation regarding medical cannabis treatment for the
Posttraumatic Stress Disorder
prevention of CINV, particularly when used in place of
dronabinol or nabilone.209 The National Comprehensive There is limited and inconsistent evidence supporting the
Cancer Network 2017 Clinical Practice Guidelines for use of medical cannabis for the treatment of posttraumatic
Antiemesis recommend the use of dronabinol or nabilone stress disorder (PTSD).231-250 There appears to be a complex
among other antiemetic medications but do not comment on relationship between PTSD and cannabis use; a strong asso-
the use of nonpharmaceutical cannabis-based products.210 ciation between the two has been demonstrated, and greater
PTSD severity has been correlated with more frequent can-
nabis use.232-234,239,242,243,245,251 Although several survey-
Pain based studies indicate that patients with PTSD report using
The available body of literature suggests that medical can- medical cannabis specifically as treatment, a prominent
nabis may be effective for the treatment of various non– hypothesis is that cannabis facilitates self-medication or
cancer-related pain disorders.15,109,211-215 Depending on the symptom avoidance.234,241-243,251 Thus, it remains unclear if
product, formulation, and concentration used in the study, medical cannabis has a beneficial therapeutic effect in miti-
between 26% and 88% of patients achieved ≥30% decrease gating PTSD symptoms or if the agent is used as a means of
in pain scores, with a NNT of between 3 and 20 patie avoidant coping.234,241-244,251 No randomized controlled tri-
nts.109,213-220 Trials demonstrated overall positive effects for als describing medical cannabis for the treatment of PTSD
medical cannabis in the treatment of chronic noncancer were identified. Current evidence is limited to survey-based
pain as well as in neuropathic pain,15,109,213,219,220 including studies, retrospective cohort studies, and small open-label
fibromyalgia,221 cancer-related pain,70,72 and rheumatic dis- studies and case reports.231-240 These studies are based on
eases.166,222 A notable exception is diabetic neuropathy, subjectively reported outcomes and are inherently suscep-
where the effect is inconsistent.223,224 Data also suggest tible to bias. Moreover, the results of these studies are
improvements in sleep quality and subjective assessment of equivocal. There are data, however, suggesting that both
pain control.219,220,225 Nabiximols has larger and more robust cannabis-based products and nabilone may have a benefi-
clinical trials than other cannabis-based products or medi- cial effect in the treatment of PTSD-related sleep distur-
cations for use in pain.219,220,222,225 Studies suggest an effect bance and nightmares unremitting with conventional
of about a 1 to 1.5 point decrease on a 0 to 10 numeric pain pharmacological treatment.231,235,237,239,248-250 A small cross-
scale, and 26% to 28% of patients achieved ≥30% decrease over study found a significant reduction in Clinician
in pain scores.219,220,222,225 This analgesic effect was observed Administered Posttraumatic Scale Recurring and
for up to 1 year.225 No head-to-head trials comparing safety Distressing Dream Scores with nabilone compared with
or efficacy between types of medical cannabis were identi- placebo (−3.6 ± vs −1 ± 2.1; P = 0.03), and 70% of study
fied.15,211-213 No studies describing the long-term use of participants rated sleep improvement as “Very much
medical cannabis for pain were identified. improved” or “Much improved.”248 Some studies suggest
Medical cannabis for the use of pain control was gener- that there may be negative consequences in using medical
ally reported to be tolerated, though many studies suggest cannabis to treat PTSD, such as a higher likelihood of
withdrawing from PTSD treatment programs18 or a higher No clinical practice guidelines discussing the use of
level of violent behavior.245 medical cannabis in palliative care were identified.269 The
Adverse events associated with medical cannabis in PTSD College of Family Physicians of Canada recommends
patients are not well described in the current body of evi- against medical cannabis as first- or second-line therapy for
dence. In those studies reporting adverse events, most were palliative cancer pain owing to limited benefits and high
mild to moderate, with dry mouth, dizziness, headache, and risk of harm; if a provider is considering medical cannabis,
mental fogginess being the most commonly reported.231,237 he or she should recommend a pharmaceutical cannabis-
The US Veterans Affairs guideline includes a strong rec- based medication (eg, nabilone or nabiximols).270
ommendation against the use of cannabis or cannabis deriv-
atives because of the lack of efficacy evidence.252 Other Relevance to Patient Care and Clinical
current domestic and international guidelines on the treat-
ment of PTSD do not include specific recommendations on
Practice
the use of medical cannabis.253-255 In their 2018 position To our knowledge, this is the largest review of medical can-
paper, the American Psychological Association states that nabis published to date and includes evidence for a wider
there is no scientific evidence to support the use of medical variety of disease states compared with previous reviews.
cannabis as a treatment for any psychiatric illness.256 Based on data identified, the most robust evidence suggests
that medical cannabis may be effective in the treatment of
CINV, seizure disorders, MS-related spasticity, and noncan-
Terminal Illness and Hospice Care cer pain (excluding diabetic neuropathy). Overall, the avail-
Patients with terminal illnesses report experiencing many able body of published literature is conflicting and generally
symptoms, with nausea, pain, anorexia, cachexia, anxiety, limited by small sample sizes, short study durations, lack of
and depression being particularly common.67,257-259 Many comparator groups (placebo or active), and reliance on
review articles discuss the potential benefits of medical observational data and patient-reported or subjective out-
cannabis for patients with terminal illness or who are comes. In studies with a control group, a large placebo
receiving hospice or palliative care260-267; however, lim- effect was consistently observed.
ited clinical studies in the hospice/palliative care popula- An important consideration is the large variation of canna-
tion were identified. Because of the lack of data bis-based products evaluated in the studies, thereby making
specifically studied in these patients, recommendations to direct comparisons difficult. Across all studies, the most com-
use medical cannabis for terminal illnesses and in the hos- mon dosage of THC ranged from 2 to 30 mg daily, and CBD
pice population are largely extrapolated from nonpallia- dosage ranged from 0.5 to 20 mg daily. Medical cannabis
tive populations. In studies performed in patients products studied also contained varying combinations and
receiving palliative care or who had a terminal illness, the ratios of THC and CBD. Regardless of the product, gradual
results are conflicting. titration was the typical strategy used by most researchers,
Some studies described decreased pain and nausea, although even the titration strategies varied widely among
improvement in sleep disruption, reduced spasticity, and studies (eg, days vs weeks to achieve targeted dosage).
greater appreciation of food.56,57,70,71,75 It is important to Medical cannabis was generally well tolerated, with the
note that these studies all utilized different forms of medi- most common adverse effects being dizziness, somnolence,
cal cannabis and included patients with different disease dry mouth, nausea, euphoria, and memory difficulties.
states and multiple confounders. Specific adjunctive med- Specific patient populations may be at higher risk for cer-
ications and doses were also not specified. The majority of tain adverse effects such as falls, lung injury, or impaired
higher-quality studies report that treatment with medical cognition.
cannabis does not improve caloric intake (MD = 0.2; 95% Currently, medical cannabis is discussed in a limited
CI = −0.66 to 1.06; P = 0.65),67 nausea/vomiting (MD = number of clinical practice guidelines, though multiple pro-
0.21; 95% CI = −0.10 to 0.52; P = 0.19),67 pain (risk dif- fessional organizations have issued position statements.
ference = 0.07; 95% CI = −0.01 to 0.16; P = 0.07),67 and Most professional organizations warn that there is insuffi-
overall quality of life (mean Functional Assessment of cient evidence to recommend medical cannabis over other
Anorexia/Cachexia Therapy quality of life scores: dronabi- approved therapies and, therefore, do not recommend medi-
nol [98.5] vs placebo [101.8]; P = 0.704)57 or reduce daily cal cannabis at all. Notable exceptions include the
opioid use in patients receiving hospice/palliative Association of British Neurologists and National Institute
care.57,60,67,259,268 for Health and Care Excellence, which identify a role for
Across studies in patients receiving palliative care or cannabis-based therapy for MS-related spasticity, but these
who had a terminal illness, commonly reported adverse guidelines specifically refer to nabiximols (Sativex), which
effects include dizziness, disorientation, memory lessening, is an approved product in the region for which these guide-
sedation, nausea, and dry mouth.56,57,60,67,70,71,75,268 lines were intended.
Inglet et al 25
Conclusions leafly.com/news/health/qualifying-conditions-for-medical-
marijuana-by-state
As more states authorize medical cannabis for the treatment 5. National Academies of Sciences, Engineering, and Medicine.
of select medical conditions, there is an increasing need for The Health Effects of Cannabis and Cannabinoids: Current
clinical evidence describing its efficacy and safety. This State of Evidence and Recommendations for Research.
review is intended to serve as a reference for clinicians, so National Academies Press; 2017. Accessed March 17, 2019.
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7. Lexicomp Online [database online]. Updated March 2019.
in the treatment of CINV, seizure disorders, MS-related Accessed March 25, 2019. https://online.lexi.com
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cannabis–based medications that have undergone rigorous lutions.com/micromedex2/librarian
clinical trial evaluation should be preferentially recom- 9. Marinol [package insert]. Chicago, IL: AbbVie Inc; 2017.
mended in accordance with evidence-based clinical practice 10. Syndros® [package insert]. Lakewood, NJ: Insys
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12. Epidiolex® [package insert]. Carlsbad, CA: Greenwich
Authors’ Note
Biosciences, Inc; 2018.
Explanation of Similar Work: The authors presented a subsection 13. GW Pharmaceuticals. Information on obtaining Sativex®.
of the current review article (specific to literature describing medi- Accessed March 7, 2019. https://www.gwpharm.com/health-
cal cannabis for pain conditions) as a poster at the 2019 American care-professionals/sativex/prescribing-information
College of Clinical Pharmacy (ACCP) Annual Meeting. 14. Utah Medical Cannabis Act of 2018, HB 3001, 2018 Leg, 3rd
Special Sess (Ut 2019).
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Declaration of Conflicting Interests toms of dementia: an-open label, add-on, pilot study. J
The authors declared no potential conflicts of interest with respect Alzheimers Dis. 2016;51:15-19. doi:10.3233/JAD-150915
to the research, authorship, and/or publication of this article. 17. Ruthirakuhan M, Lanctôt KL, Vieira D, Herrmann N. Natural
and synthetic cannabinoids for agitation and aggression in
Funding Alzheimer’s disease: a meta-analysis. J Clin Psychiatry.
2019;80:18r12617. doi:10.4088/JCP.18r12617
The authors received no financial support for the research, author- 18. van den Elsen GA, Tobben L, Ahmed AI, et al. Effects of tetra-
ship, and/or publication of this article. hydrocannabinol on balance and gait in patients with dementia:
a randomized controlled crossover trial. J Psychopharmacol.
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Shannon Inglet https://orcid.org/0000-0001-6089-9300 19. van den Elsen GA, Ahmed AI, Verkes RJ, et al.
Tetrahydrocannabinol for neuropsychiatric symptoms
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Clinical Data For Use of Cannabis A Review

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Clinical Data for the Use of Cannabis-

Review of the Literature journals.sagepub.com/home/aop

Shannon Inglet, PharmD1 , Bradly Winter, PharmD1,

Data Sources application for nabiximols.7,8,13 Although terminology is

Study Design Duration n Interventions Primary end point results

Amyotrophic lateral sclerosis

Study Design Duration n Interventions Primary end point results

Inflammatory bowel disease (Crohn’s disease [CD], ulcerative colitis [UC])

Study Design Duration n Interventions Primary end point results

Pain (chronic noncancer, neuropathic)

Study Design Duration n Interventions Primary end point results

Table 2. (continued)

Oral Oral solution: cannabidiol (Epidiolex) 100 mg/mL

Table 2. (continued)

Inhaled Smoking: dried cannabis flower buds in cigarettes

Amyotrophic Lateral Sclerosis Commonly reported adverse events of cannabis-based

Symptom Manage. 2013;46:207-218. doi:10.1016/j.jpainsym- sclerosis complex. Epilepsia. 2016;57:1617-1624.

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