Clinical Review & Education

JAMA Otolaryngology–Head & Neck Surgery | Review

Cannabis Inhalation and Voice Disorders

A Systematic Review
Jiries Meehan-Atrash, BS; Tetiana Korzun, BS, BA; Aaron Ziegler, MA, PhD, CCC-SLP

Audio and Supplemental

IMPORTANCE Widespread legalization of cannabis throughout the United States has created a content
knowledge gap that leaves practitioners who manage voice disorders uninformed about this
substance, commonly referred to as marijuana. The association of cannabis inhalation and
voice disorders is rarely reported. However, studies on the association between cannabis
inhalation and respiration have been published; therefore, these studies may serve as a
surrogate for studies on the association between cannabis and phonation.

OBJECTIVE To review the literature on the association of cannabis-only consumption via

smoking and vaping with the health and function of the vocal mechanism to aid clinical
recommendations for patients with voice disorders.

EVIDENCE REVIEW This systematic review adhered to the Preferred Reporting Items for
Systematic Reviews and Meta-analyses statement. An electronic search in MEDLINE via
PubMed, CINAHL, Scopus, and Cochrane Library databases for original research on inhaled
cannabis was performed from January 1, 2007, through August 10, 2018. The search strategy
included Medical Subject Heading terms and keywords marijuana, cannabis, respiratory,
lungs, larynx, voice, phonation, and vocal with Boolean operators (AND, OR). Studies of
participants of legal age (ⱖ18 years) who had cannabis-only clinical data and used
nonsynthetic cannabinoids were included in the review.

FINDINGS This systematic review identified 6 clinical science studies and 13 basic science or
animal studies. The only study to date that has evaluated the association between laryngeal
symptoms and inhaling cannabis found that human smokers assessed by indirect
laryngoscopy with mirror examination exhibited dark vocal folds. Analyses of 6 other clinical
science articles indicated an association between cannabis inhalation and respiratory
problems that were reduced with smoking cessation or switching to vaporizing. Lung
function was maintained in light cannabis smoke exposure after long-term use. Analyses of
basic science and animal articles indicated that cannabis smoking was associated with lung
and throat injuries attributable to smoking degradation byproducts, similar to injuries seen in
human tobacco smoking.

CONCLUSIONS AND RELEVANCE The findings suggest that cannabis-only smoking is associated
with changes in vocal fold appearance, respiratory symptoms, and negative lung function
changes, especially in heavy smokers. Details about patterns of cannabis consumption appear
to be relevant to gather in patients with voice disorders. Results further suggest that cannabis
Author Affiliations: Department of
smokers presenting with a voice disorder should undergo laryngeal imaging and complete Chemistry, Portland State University,
pulmonary function testing when indicated and receive education about consumption Portland, Oregon (Meehan-Atrash);
methods and their association with voice disorders. Department of Otolaryngology,
Oregon Health & Science University,
Portland (Korzun); School of
Medicine, Department of
Otolaryngology–Head & Neck
Surgery, Oregon Health & Science
University, Portland (Ziegler).
Corresponding Author: Aaron
Ziegler, MA, PhD, CCC-SLP,
Department of Otolaryngology–Head
& Neck Surgery, Oregon Health &
Science University, 3181 SW Sam
Jackson Park Rd, Ste SJH01,
JAMA Otolaryngol Head Neck Surg. doi:10.1001/jamaoto.2019.1986 Portland, OR 97239-3098
Published online August 8, 2019. (asziegler@gmail.com).

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 Clinical Review & Education Review
N
early half the population in the United States has tried
cannabis.1 In 2014, 19.6% of US adults aged 18 to 25 years
and 6.6% of US adults 26 years or older were past-
month cannabis consumers.1 Past-year cannabis consumption in-
creased in US adults 18 years or older from 10.4% in 2002 to 13.3%
in 2014.2 In Canada, where cannabis was legalized for adult recre-
ational consumption in 2018, 12.5% of persons 15 years or older re-
ported consuming cannabis in the past 3 months.3 Public aware-
ness and passage of cannabis laws have led to reduced perceived
risk of harm, which was associated with increased prevalence in past-
year consumption from 2002 to 2014.2 Accordingly, practitioners
managing voice disorders need information about the association
of cannabis with voice disorders for making sound recommenda-
tions on its consumption. To our knowledge, the association be-
tween cannabis smoking and voice disorders has only been stud-
ied once.4 More studies5-7 have addressed the association between
cannabis consumption and disorders of the respiratory system, the
function of which is vital to regulating air pressure and airflow for
voice.8 The findings of those studies5-7 may serve as a surrogate for
some aspects of the association between cannabis and phonatory
disorders.
Cannabis (and its preparations) can be delivered via oral, der-
mal, or inhalation methods. Inhaling smoke from dried inflores-
cences (ie, flowers or buds) using a joint (a cannabis cigarette, typi-
cally filterless and generally available in 0.5- to 1.0-g units), a cannabis
pipe, or a cannabis water pipe remains the most popular method be-
cause of ease of use, availability, and rapid response onset.9 Can-
nabis smoking topography differs significantly from tobacco; can-
nabis smokers use large inhalation volumes and breath-holding to
extract maximum amounts of Δ9-tetrahydrocannabinol (THC) be-
fore exhaling.5 Analogous to pack-years with tobacco, cannabis
smoking is measured using the joint-year, which is defined as smok-
ing 1 joint per day for 1 year.5,10,11 The joint-year accounts for need-
ing less consumption to achieve the desired response compared with
tobacco smoking.
In the lungs, cannabinoid receptors are located on structural cells
and leukocytes.12 The endocannabinoid system, involved in regu-
lating physiologic and cognitive processes,13,14 primarily consists of
endogenous ligands (endocannabinoids), cannabinoid receptors (eg,
cannabinoid receptor 1 [CB1R], cannabinoid receptor 2 [CB2R]), and
degradative enzymes.14 The CB1Rs are primarily expressed in the cen-
tral nervous system and activated by THC, a CB1R and CB2R partial
agonist responsible for the psychoactive effect of cannabis.15 The
CB2Rs are most abundantly expressed in tissues related to immune
function14 but are highly inducible under conditions of injury or
inflammation.16 The endocannabinoid system and its modulators
may play a critical role in disorders managed by otolaryngologists
because of adverse manifestations or therapeutic benefits of can-
nabis consumption.17
Urine biomarkers for toxic combustion byproducts were found
at high levels in cannabis smokers, and many also had tobacco-
specific markers.18 This risk of coexposure to tobacco stems from
second-hand smoke or from mixing cannabis with tobacco in a ciga-
rette with a mix of cannabis buds, hashish (a resinous extract), or
cannabis flower rolled in a cigar wrapper. Several toxic constitu-
ents of tobacco smoke were found at higher levels in cannabis smoke
(eg, ammonia, hydrogen cyanide nitric oxide, and aromatic amines).19
An alternative to smoking, vaporizing cannabis flowers or cannabis
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Cannabis Inhalation and Voice Disorders
Key Points
Question What is the association between cannabis inhalation
and voice disorders?
Findings In this systematic review of 6 human studies and 13
basic science and animal studies, cannabis inhalation was
associated with dark vocal folds on laryngoscopy as well as
respiratory symptoms and negative lung function changes
attributable to degradation byproducts generated during smoke
exposure, especially in large doses. Cessation of cannabis
consumption or changing to vaporizing methods was associated
with improved respiratory symptoms and lung function changes.
Meaning The findings suggest that practitioners managing voice
disorders should gather details about patterns of cannabis
consumption and that cannabis smokers with a voice disorder
should undergo laryngeal imaging and complete lung function
testing when dyspnea is present and receive education about the
potential negative effects of inhalation.
extracts (eg, butane hash oil) has gained in popularity.20 Although
vaporizing cannabis has been touted as safer than smoking, ex-
tract consumption via dabbing (a method of inhaling vaporized bu-
tane hash oil)21 may generate appreciable levels of aldehydes and
benzene22 that are suspected to cause airway cancers.23
Recent changes to the legal status of cannabis have outpaced
research about its association with voice disorders. We present
the first systematic review (that we are aware of) to assess the
association of cannabis-only consumption with the health and
function of the vocal mechanism. We hypothesized that cannabis
inhalation would be associated with chemical injury to the voice
attributable to inhaling degradation byproducts, thermal injury
with high inhalation temperatures, and biomechanical injury from
coughing.
Methods
Information Sources and Search Strategy
This systematic review focused on any associations between
inhalation of cannabis and voice disorders. The review protocol
was consistent with the Preferred Reporting Items for Systematic
Reviews and Meta-analyses (PRISMA) reporting guideline. In
consultation with a research librarian, we performed an electronic
search in MEDLINE via PubMed, CINAHL, Scopus, and Cochrane
Library databases from January 1, 2007, to August 10, 2018, the date
of the most recent search. This date range was chosen to exclude
older studies that likely differ from contemporary research because
of changes in strain varieties, cannabinoid and terpene profiles, and
large increases in THC content over time.24 Studies in a language
other than English were excluded. The search strategy included
Medical Subject Heading terms and keywords marijuana, cannabis,
respiratory, lungs, larynx, voice, phonation, and vocal with Boolean
operators (AND, OR).
Selection of Studies and Eligibility Criteria
Three reviewers (J.M.-A., T.K., and A.Z.) independently screened
all titles and abstracts and divided clinical from basic science
jamaotolaryngology.com
 Cannabis Inhalation and Voice Disorders Review Clinical Review & Education

Table 1. Results of Clinical Study Quality Assessment Using National Institutes of Health Quality Assessment Toolsa
Exposure Before
Outcome/
Participation Time for
Study Rate >50%/ Exposure- Exposure Assessors Confounding
Objective Representa- Outcome Defined or Blinded to Variables
Clear/ tiveness of Association/ Described/ Exposure or Measured
Study Participants/ Assessed Levels Exposure Outcomes Statistics or Results
Population Sample Size of Exposure on Assessed Clearly Cleary Follow-up Clearly
Study Study Design Defined Justification Outcome Repeatedly Defined Described <20% Described Total Rating
Pletcher et al,6 Cohort +/+ +/+/+ +/+/+ +/+ + NR + + 13 of 14
2012
Tashkin et al,26 Cohort +/+ +/+/− +/+/− +/+ + NR − + 10 of 14
2012
Van Dam and Cohort +/+ CD/+/− +/+/− +/+ + NR + + 10 of 14
Earleywine,27
2010
Tan et al,7 2009 Cross-sectional +/+ NA/+/+ −/+/− +/− + NR NA + 9 of 14
Aldington et al,5 Cross-sectional +/+ +/+/− CD/+/+ +/+ + + NA + 11 of 14
2007b
Hii et al,25 2008c Case series +/+ CD/−/NR NR/NA/NR +/NR + + NR + 6 of 9
No. of studies NA 6/6 4/5/2 of 5 3 of 5/5/2 of 5 6/4 of 5 6 2 2/5 6 NA
Abbreviations and symbols: CD, cannot determine; NA, not applicable; NR, not differed at each time point.
reported. c
In the case series study,25 NR indicates that quality criteria account for fewer
a
Minus signs indicate that the criterion was not met; plus sign, criterion met. items in this tool than the one for cohort and cross-sectional studies (9 vs 14
b
Doses and exposure were self-reported by participants; data were available quality criteria, respectively).
only for a cross-section of participants from a larger cohort study, which

and animal research. Of the clinical research, observational and

interventional studies were included; case reports were removed.
Clinical science studies were excluded if participants were
younger than 18 years. The remaining articles were reviewed for
cannabis-only data, after which 6 articles of clinical research
remained. Basic science and animal studies that used only syn-
thetic cannabinoids were excluded, with 13 remaining for analysis.
The eFigure in the Supplement shows the literature selection pro-
cess.
Data Collection and Data Items
Data for clinical science studies were extracted for sample size,
sex, age, tobacco use status, frequency and quantity of cannabis
consumption, spirometric data, and notes on symptoms and find-
ings. Cannabis-only data were extracted by collating available
data (J.M.-A., T.K.), and variables (eg, age) were recalculated for
cannabis-only participants. Data extracted from Hii et al25 were of
former tobacco smokers (1-7 years of smoking), and Tashkin
et al26 differentiated between cannabis-only and other smoking
categories (Table 1). Basic science and animal data included ana-
lyte, experimental substrate, measure or variable tracked, and
findings on the association between cannabinoids or marijuana
smoke condensate (MSC) and the respiratory system.
Risk of Bias in Studies
An assessment of clinical study quality was performed indepen-
dently by 2 raters (T.K., A.Z.) using tools developed by the
National Heart, Lung, and Blood Institute at the National Insti-
tutes of Health. Different tools were used for cohort and cross-
sectional study designs vs case series.28 Consensus was reached
on the few rater discrepancies that emerged. A formal assess-
ment of basic science study quality was not completed because of
a lack of published tools for nonanimal research.
Results
Quality of Study and Risk of Bias
This systematic review identified 6 clinical science studies5-7,25-27 and
13 basic science and animal studies.29-41 The study quality assess-
ment (Table 1) revealed significant heterogeneity in study design and
strength of evidence among clinical science studies. Three clinical
science studies6,26,27 were cohort design, 2 were cross-sectional,5,7
and 1 was a case series.25 Cohort and cross-sectional studies were
mostly of fair quality, although 1 prospective cohort study6 was of
high quality. Three studies5,6,26 had large data sets of participants
(>70 participants) (Table 2); 3 studies7,25,27 contained fewer than 19
participants. In all human studies, cannabis and tobacco consump-
tion were determined by self-report. Although studies that did not
account for tobacco use were excluded, unforeseen interactions with
other drugs or environmental factors were not considered. Areas of
weakness included lack of exposure levels, details on assessor blind-
ing, and sample size justification, as well as poor ability to establish
an association (exposure was not measured before outcome in 3
studies). In terms of basic science and animal study quality, hesita-
tion is necessary when considering results obtained using MSC or
cannabis smoke because varying cannabinoid and degradant con-
centrations attributable to diversity in starting material and puff pro-
file may lead to between-study variability (Table 3).
Synthesis of Clinical Science Research
This systematic review examined published data on cannabis inha-
lation from 6 clinical science studies.5-7,25-27 Although the study by
Mueller and Wilcox4 was not formally entered in the review be-
cause it was published 27 years earlier, the objectives and associa-
tions (with voice) in this study are relevant enough to warrant in-
clusion. Participants were nonsmoking controls for the past 3 years

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 Clinical Review & Education Review Cannabis Inhalation and Voice Disorders

Table 2. Clinical Study Variables and Characteristics of Individuals Who Inhaled Only Cannabis
No. of
Study Partici-
Study Designa pants Sex Age, y Tobacco Use Cannabis Consumption Main Findings
Pletcher et al,6 Cohort 795 55% M Range, NA Yes or no Difference compared with reference value
2012 18-30 of +0.7 mL for FEV1and +8.2 mL for FVC
Tashkin et al,26 Cohort 72 M and F Mean Mean (SD), 3.2 Mean (SD), 62.1 Respondents lost vs gained bronchitis
2012 (SD), (1.3) pack-years (20.4) joint-yearsb symptoms after a mean (SD) of 9.4 (0.5) y;
31.8 cough: 62.5% vs 11.1%; sputum: 61.1% vs
(0.6) 13.2%; acute bronchitis: 81.8% vs 11.7%;
wheeze: 77.8% vs 19.2%
Van Dam and Cohort 12 M and F Mean NA Mean (SD), 6.5 (1.0) Mean (SD) FEV1/FVC: 70.9% (48.1%); 26.1%
Earleywine,27 (SD), d/wk reported respiratory distress
2010 20.4
(1.4)
Tan et al,7 2009 Cross-sectional19 M and F Mean NA Yes or no; having AOR (95% CI) for risk of COPD as diagnosed
(SD), smoked >50 marijuana by spirometric testing: 1.66 (0.52-5.26);
65.2 cigarettes self-report: 0.62 (0.31-1.27); physician
(9.1) diagnosis: 0.67 (0.09-5.29)
Aldington et al,5 Cross-sectional75 89% M Mean NA Yes or no Mean (SD) FEV1: 4.17 (0.7) L; mean (SD)
2007 (SD), FEV1/FVC: 76.2% (6.6%); cannabis attenuated
42.5 FEV1 reduction from tobacco; cannabis
(9.7) associated with increased percentage of
low-density lung tissue
Hii et al,25 2008 Case series 4 M Mean Ex–tobacco Mean (SD), 19.2 Mean (SD) FVC: 80.2 (24.0); mean (SD)
(SD), smokers (1-7 y) (10.7) joint-years FEV1/FVC: 53.5 (7.9)
43.5
(10.7)
Abbreviations: AOR, adjusted odds ratio; COPD, chronic obstructive pulmonary Pletcher et al6 is a longitudinal study of 20 years, but the cannabis-only data
disease; FEV1, forced expiratory volume in 1 second; FVC, forced vital capacity; are cross-sectional in nature.
NA, not applicable. b
Baseline value; follow-up data on joint-years were not given.
a
Data type for the cannabis-only subsets of the data for each study. Specifically,

Table 3. Study Variables of Basic Science and Animal Research

Source Analyte Substrate

Abdel-Salam et al,36 Cannabis extract Swiss male albino mice
2013
Helyes et al,34 2017 Cannabis smoke CB1R knockout mice and WT mice
Davies et al,35 2017 MSC Curosurf, porcine pulmonary surfactant in a lung
biosimulator
Kim et al,31 2012 MSC WT human lung cells and p53 gene–inhibited human
lung cells
Kim et al,32 2013 MSC p53-WT lung cancer cells and p53-null
adenocarcinoma cells
33
Maertens et al, 2013 MSC and TSC Murine pulmonary epithelial cells
Abbreviations:
Dudášová et al,38 2013 CBD Guinea pig bronchial smooth muscles and bronchi CBC, cannabichromene;
41
Ribeiro et al, 2012 CBD Murine model of acute lung injury CBDA, cannabidiolic acid;
Chang et al,29 2018 THC Bronchial epithelial cells and HAEC CBD, cannabidiol; CBG, cannabigerol;
CB1R, cannabinoid receptor type 1;
Grassin-Delyle et al,37 THC Human bronchi, ex vivo CB2R, cannabinoid receptor type 2;
2014
HAEC, human airway epithelial cell;
Preet et al,40 2008 THC NSCLC cells, tumor xenografts in immunodeficient MSC, marijuana smoke condensate;
mice
NSCLC, non–small cell lung cancer;
30
Sarafian et al, 2008 THC, MSC, and TSC Cellular model of human lung epithelial; THC, Δ9-tetrahydrocannabinol;
CB2R-transduced cells
THCV, tetrahydrocannabivarin;
Makwana et al,39 2015 THC, CBD, CBG, CBC, CBDA, and Guinea pig–isolated trachea, male adult guinea pigs TSC, tobacco smoke condensate;
THCV WT, wild-type.

(1 male and 10 females), tobacco smokers who had at least 1 pack of
cigarettes per day (1 male and 9 females), and cannabis smokers who
consumed cannabis at least weekly for the past 3 years and who had
not smoked tobacco during that same period (7 males and 7 fe-
males). Vocal pitch and voice quality auditory-perceptual ratings by
naive and trained listeners fell within normal limits; fundamental fre-
quencies also fell within normal limits for age and sex. Darker vocal
folds were observed on indirect laryngoscopy using a mirror in 8 of
12 participants who were cannabis smokers compared with con-
trols and tobacco smokers with normal laryngoscopy examination
findings. Although only cannabis smokers were observed with dark
vocal cords, it was not possible to visualize the vocal cords for 2 of
the 14 cannabis smokers, 2 of the 11 nonsmokers, and 5 of the 10 to-
bacco smokers. Tissue sample testing was suggested, but no com-
ments were made about results. Some participants reported strain
or hoarseness when queried about the effect of cannabis on their
voice during times that they smoked it.
Several studies identified a negative association between can-
nabis inhalation and respiration. Hii et al25 described a series of 10
cannabis smokers admitted to a hospital with lung injury. Four re-

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 Cannabis Inhalation and Voice Disorders
ported that they were former tobacco smokers (1-7 years of cessa-
tion), whereas the remainder indicated that they currently smoked
tobacco. Among the past tobacco smokers, high-resolution com-
puted tomography showed severe bullae, and spirometry indi-
cated moderate to severe airflow obstruction. Aldington et al5 com-
pleted secondary analyses using a cross-section of data collected as
part of a larger cohort study. They found that lower lung density was
associated with cannabis smoking. In regard to airflow obstruc-
tion, 1 cannabis joint was equivalent to smoking 2.5 to 5.0 ciga-
rettes. The authors attributed changes to the way cannabis was
smoked, using large inhalation volumes and breath-holding at full
capacity with the Valsalva maneuver. Their conclusions were that can-
nabis in amounts smoked in New Zealand was not a contributor to
emphysema.
Although the above studies identified negative outcomes, oth-
ers reported milder lung function response to cannabis smoking.
Pletcher et al6 reported a nonlinear association between forced vi-
tal capacity (FVC)/forced expiratory volume in 1 second (FEV1) ra-
tio and cannabis inhalation, showing a positive trend below 10 joint-
years that plateaued and reversed with more intense consumption.
Although the data set contained only a few heavy cannabis smok-
ers, a positive association was also found in a mixed set of cannabis-
only and cannabis plus tobacco smokers. Tan et al7 did not identify
an association between cannabis smoking and chronic obstructive
pulmonary disease (COPD).
With regard to long-term findings, Tashkin et al26 sought to iden-
tify the association of continuing or quitting cannabis and tobacco
smoking with bronchitis symptoms. Participants who quit smoking
either or both tobacco and cannabis were more likely to have fewer
bronchitis symptoms on follow-up. Spirometric data from the same
cohort42 indicated that an annualized rate of change in FEV1 for can-
nabis-only smokers was identical to that in nonsmokers. Tashkin
et al26 noted that central airway edema, indicated by elevated air-
way resistance, may have been responsible for increased coughing
and wheezing in the cannabis-only group. Van Dam and Earleywine27
examined whether switching exclusively to vaporizing cannabis (a
noncombustion method) would be associated with fewer respira-
tory symptoms than smoking cannabis (a combustion method). Va-
porizing was associated with decreased respiratory symptoms, a sta-
tistically significant mean (SD) increase in FVC (0.22 [1.6] L; P = .007),
and a nonstatistically significant mean (SD) increase in FEV1 (0.38
[1.5] L; P = .047).
Synthesis of Basic Science and Animal Research
The published data from 13 basic science and animal studies29-41 were
examined to appreciate mediating factors for voice changes asso-
ciated with cannabis inhalation, although findings cannot be imme-
diately translated to humans (Table 4). Several studies found that
cannabis smoke exposure may be associated with significant air-
way toxic effects. Chang et al29 found that human airway epithelial
cells exposed to THC expressed lower amounts of cystic fibrosis
transmembrane conductance regulator, a mucous membrane regu-
lator that is dysfunctional in cystic fibrosis.43 Sarafian et al30 found
that THC was associated with reduced chemotaxis in human lung
epithelial cells, which is vital to immune response and repair; THC
also affected cellular energetics through mitochondrial injury. Kim
et al31,32 found that MSC was associated with chromosomal dam-
age and oxidative stress that led to apoptosis. Maertens et al33 found
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Review Clinical Review & Education
that MSC was associated with similar molecular pathways as to-
bacco smoke condensate (TSC) but was more potent. Helyes et al34
reported a negative association of cannabis smoking with lung func-
tion and histopathologic findings that were not CB1R mediated and
suggested that this was attributable to pyrolysis products because
wild-type and CB1R knockout mice responded equally to cannabis
smoke. In addition, Davies et al35 found that the hydrophobicity of
THC was negatively associated with the properties of the lungs’ sur-
factant layer and with reduced alveolar stability, potentially leading
to restricted lung mechanics and increased risk of conditions such
as COPD44 or localized infections.45
Abdel-Salam et al36 studied effects of intraperitoneal cannabis
administration in mice alone and in conjunction with systemic lipo-
polysaccharide (LPS) administration using several markers of oxi-
dative stress (malondialdehyde [MDA], glutathione [GSH], and ni-
tric oxide [NO]) and histopathologic and immunohistochemical
staining in several organs, including the lungs. Cannabis alone had
no significant effects on MDA, GSH, or NO levels in the lungs. Can-
nabis administered to LPS-treated mice produced a decrease in MDA
and NO but an increase in GSH. For the histopathologic studies, LPS
administration indicated observable thickening of some alveolar
capillary membranes and focal hemorrhage, whereas LPS and
cannabis–treated mice had intense congestion and dilation of blood
vessels, inflammation, diffuse alveolar collapse, and alveolar wall
thickening.
Evidence was presented for use of cannabinoids as therapeu-
tic agents.17 Grassin-Delyle et al37 found that inhibition of choliner-
gic contractions by THC were CB1R mediated and may be associ-
ated with acute bronchodilation after cannabis consumption.
Dudášová et al38 found that cannabidiol (CBD), a nonpsychoactive
phytocannabinoid, was associated with reduced antigen-induced
bronchoconstriction, although contractions were potentiated at
higher concentrations. Makwana et al39 sought to probe possible syn-
ergies among 6 phytocannabinoids on bronchoconstriction using in
vitro and in vivo methods. The THC alone had antitussive and anti-
inflammatory properties. THC plus CBD was associated with a com-
plete cessation of tumor necrosis factor α–augmented electrical field
stimulation contractions, and tetrahydrocannabivarin was associ-
ated with only a partial reduction. Preet et al40 observed THC to have
antitumorigenic and antimetastatic properties on non–small cell lung
cancer. Ribeiro et al41 revealed that single doses of intraperitoneal
CBD had a potent anti-inflammatory association with LPS-induced
lung injury in mice.
Discussion
This systematic review examined published research to assess the
association between inhaled cannabis and voice disorders. One
study4 directly addressed changes to voice; however, results were
limited in scope. Studies5-7,25-27 evaluating the association of can-
nabis inhalation with respiratory tract health were reviewed as well;
findings from respiratory data about a potential association of can-
nabis inhalation with voice disorders are speculative. The associa-
tion of cannabis smoking with airway disorders does not appear to
follow a linear trend, unlike tobacco. Two contrasting factors may
account for the nonlinearity observed with cannabis inhalation and
airway function: (1) a tendency to increase airway resistance and air-
E5
 Clinical Review & Education Review
Table 4. Study Findings of Basic Science and Animal Research by Analyte Used
Study Experimental Measures
Abdel-Salam et al,36 MDA, GSH, and NO as markers of oxidative
2013 stress and organ damage after
administration of LPS and/or cannabis
extract; histopathologic studies and
immunohistochemical staining of affected
organs after administration of LPS and/or
cannabis extract
Helyes et al,34 2017 Bronchial responsiveness, markers of
inflammation, histopathologic changes
Marijuana Smoke Condensate
Davies et al,35 2017 Langmuir maximum surface pressure and
compressibility
Kim et al,31 2012 Effects of p53 on genotoxicity, ROS
formation, and apoptosis as a result of
MSC exposure
Kim et al,32 2013 Markers of apoptosis, ROS generation,
SOD and catalase enzyme activity
Maertens et al,33 Cytotoxicity, gene expression profiling,
2013 benchmark dose modeling
Cannabidiol
Dudášová et al,38 Contractile responses of bronchial smooth
2013 muscle from OVA-sensitized guinea pigs
were investigated in the absence or
presence of CBD; effects of ECBs, TRPV1
agonist, and FAAH
Ribeiro et al,41 2012 Inflammation as monitored by leukocyte
trafficking, myeloperoxidase activity,
proinflammatory cytokine and chemokine
analysis, vascular permeability
Δ9-Tetrahydrocannabinol
Chang et al,29 2018 Effect of THC on CFTR protein expression;
assessment of the role of ERK/MAPK
pathway on effect of THC on CFTR
Grassin-Delyle Bronchial reactivity as measured by
et al,37 2014 EFS-induced cholinergic contraction
Preet et al,40 2008 Effects of THC on EGFR on NSCLC and on
metastasis and tumorigenesis on NSCLC
Sarafian et al,30 2008 Chemotaxis, mitochondrial membrane
potential, cellular ATP levels, intracellular
signaling protein monitoring
Makwana et al,39 In vivo effects on bronchoconstriction
2015 and cough; in vitro effects on TNF-α and
LPS-induced leukocyte infiltration in
the lungs
Abbreviations: ATP, adenosine triphosphate; CBD, cannabidiol;
CB1R, cannabinoid receptor type 1; CB2R, cannabinoid receptor type 2;
CFTR, cystic fibrosis transmembrane transport receptor; EFS, electrical field
stimulation; EGFR, epidermal growth factor; FAAH, fatty acid amide hydrolase;
GSH, glutathione; LPS, lipopolysaccharide; MDA, malondialdehyde;
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Cannabis Inhalation and Voice Disorders
Main Findings Notes
Intraperitoneal administration of cannabis No results from immunohistochemical
extract had no significant effect on MDA, staining were mentioned for the lungs
GSH, or NO in lung tissue; histopathologic
analysis after LPS administration indicated
observable thickening of alveolar capillary
membranes, whereas LPS and
cannabis–treated mice had intense
congestion and dilation of blood vessels,
inflammation, diffuse alveolar collapse, and
alveolar wall thickening
Daily cannabis smoke exposure induced Respiratory effects were not attributable
airway hyperreactivity, edema, atelectasis, to CB1R activation
emphysema, neutrophil macrophage
infiltration, lymphocyte accumulation, and
irregular bronchial mucosa
MSC reduced surface tension and increased Compression and expansion cycling
compressibility in Curosurf relative to analogous to tidal breathing had a
unadulterated pulmonary surfactant protective effect against the increase in
compressibility
MSC-induced genotoxicity, ROS formation, p53 Plays an important role in cellular
and apoptosis are statistically higher in response to MSC
p53-WT and p53-null cells
MSC dose-dependently increased No notes
cytotoxicity; p53 and other
apoptosis-related genes appear to be
involved in this process; MSC increases ROS
generation, likewise SOD and catalase
enzymes are activated by MSC
MSC is more potent than TSC in expressing No notes
genes associated with xenobiotic
metabolism, oxidative stress, inflammation,
and DNA damage
CBD’s influence on antigen-induced The effect of CBD on airways may be
contractions on airway smooth muscle is related to mast cell degranulation
indirect and may act through multiple
targets, including TRP channels and FAAH
inhibitors, but it is not mediated by
histamine
CBD decreases leukocyte migration to the Adenosine A2A signaling mediates
lungs, decreases myeloperoxidase activity, anti-inflammatory response
and decreases proinflammatory cytokine
and chemokine production
THC decreased CFTR protein expression in Only higher doses of THC resulted in
primary human bronchial epithelial cells and sustained upregulation of ERK expression
appears to mediate this effect via activation
of the ERK/MAPK pathway
THC inhibits cholinergic contraction in a Inhibition of EFS-induced cholinergic
concentration-dependent manner contraction is CB1R mediated
In vitro results: THC inhibits EGFR-induced No notes
migration, invasion, and proliferation; in
vivo results: tumor growth, proliferation,
and vascularization in THC-treated mice
were significantly inhibited compared with
controls
THC and MSC suppressed chemotaxis, THC’s effects on airway epithelial cells
whereas TSC did not; THC decreased ATP are only partially mediated by CB2R
levels and mitochondrial membrane
potential
THC reduced bronchoconstriction and cough No notes
in vivo; in vitro tracheal contractions were
reduced to background levels by THC and
THC plus CBD but only partially reduced by
THCV; other cannabinoids were without
effect; THC reduced neutrophil
accumulation in the lungs; only THCV
reduced LPS-induced neutrophilia
MSC, marijuana smoke condensate; NO, nitric oxide; ROS, reactive oxygen
species; SOD, superoxide dismutase; THC, Δ9-tetrahydrocannabinol;
THCV, tetrahydrocannabivarin; TRP, transient receptor channel;
TSC, tobacco smoke condensate; WT, wild-type.
jamaotolaryngology.com
 Cannabis Inhalation and Voice Disorders
flow obstruction and (2) a tendency for improved lung function as
assessed by spirometry. These results provide practical informa-
tion for practitioners treating patients who consume cannabis and
present with voice disorders.
Cannabis Inhalation: Tendency
for Increased Airway Resistance
Increased airflow resistance and symptoms of respiratory distress
were reported in most of the studies, especially in heavy cannabis
consumers (>10 joint-years). The finding in the study by Aldington
et al5 that 1 cannabis joint produced 2.5 to 5.0 times the airflow ob-
struction of 1 cigarette aligns with the findings that MSC was more
potent than TSC in inducing genes related to inflammation and oxi-
dative stress33 and that cannabis smoke had higher levels of gas-
phase toxins.19 Smoke toxins may contribute to chronic respira-
tory system damage, and the way in which cannabis is smoked may
contribute to acute and chronic barotrauma implicated in sponta-
neous pneumothorax25 and decreased lung density.5 Cannabis smok-
ing was associated with respiratory symptoms, such as morning
cough, sputum production, and wheezing.46 Respiratory symp-
toms appeared to follow a dose-response relationship that was more
strongly associated with frequency of consumption rather than the
quantity consumed.47 Changes to lung parenchyma would likely re-
quire greater expiratory forces for voicing that may increase the work
of breathing and potentially lead to speaking-related dyspnea.48
Muscle tension dysphonia may be a voice disorder associated with
smoking cannabis because lung hyperinflation in COPD challenges
the larynx’s control of phonatory resistance.48 Considering these
findings as a whole, cannabis smoking appears similar to tobacco
smoking in its potential deleterious consequences on voice; both may
be associated with (in a dose-response relationship) airway inflam-
mation, congestion, and cough.49,50
Although cannabis appears to have significant toxic effects even
when compared with tobacco smoke, results from the study by He-
lyes et al34 implied that negative changes were associated with com-
bustion byproducts and not from pharmacologically active constitu-
ents of cannabinoids. However, cannabinoids are not without an
association with lung epithelial cells. Sarafian et al30 suggested that
THC may suppress chemotaxis,51 a process thought to play a role in
repair and response to outside injury.30 One possible hypothesis with
such findings is that cannabis consumption by any route, inhala-
tion or otherwise, may alter vocal fold wound healing responses af-
ter repeated vibratory microinjury during voice production (ie,
phonotrauma).52-55 In addition56-58, THC had a negative effect on
the lungs’ surfactant layer, which was hypothesized to restrict lung
mechanics attributable to difficulty with alveolar expansion, indi-
cating that inhaled aerosols with higher THC content may be more
damaging.35 Cannabis vaporizers have not been evaluated for safety.
Van Dam and Earleywine27 found that switching from smoking to
vaporizing may reduce respiratory symptoms. However, cannabis
constituents, such as CBD and terpenes, under vaporizing condi-
tions may release oxidation products.22,59
Cannabis Inhalation: Tendency for Improved Lung Function
Despite60 potential lung toxic effects, increase and preservation of
pulmonary function seen in cannabis smokers have been consis-
tently observed in clinical studies,6,25,26 especially when com-
pared with tobacco smokers.61 Bronchodilation, which has a well-
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Review Clinical Review & Education
documented association with cannabis, has been offered as an
explanation.62-65 This explanation is consistently dismissed, how-
ever, given improvements in FEV1 after long-term treatment with
anticholinergic bronchodilators.5,6,10,65-67 The mechanism of ac-
tion of THC differs from anticholinergics,37,68,69 and long-term ef-
fects of CB1R agonist–mediated bronchodilation specifically have not
been studied. Alternatively, multiple studies5,6,10,66 suggest that
large, repeated inhalation volumes when smoking cannabis may
stretch the lungs and exercise respiratory musculature, leading to
increased FVC. Findings from Dudášová et al38 indicate that CBD was
associated with reduced antigen-induced bronchial contractions,
pointing to the usefulness of this compound for potentially treat-
ing asthma and respiratory inflammatory conditions that in turn could
hinder phonation.48,67
Research on the potential of cannabis to cause airway obstruction
is somewhat conflicting. Spirometric data indicate that cannabis smok-
ers have slightly higher airway resistance and modestly lower specific
airway conductance compared with nonsmokers, which may be ex-
plained by secretions and upper airway congestion.66 A 2010 epide-
miologic study10 noted that cannabis smoking was associated with not
only higher airway resistance but also increased FVC, total lung capac-
ity, and residual volume; hyperinflation was suggested as causing ob-
served increases in airway resistance. A 2015 cross-sectional study61
suggested that cannabis smoking is associated with increases in the
risk of an FEV1/FVC ratio less than 70% attributable to increased FVC
rather than decreased FEV1. This finding was seen in participants with
a consumption history greater than 20 joint-years but was absent be-
low this threshold.
Clinical Recommendations for Voice
This systematic review suggests that patients who inhale cannabis
may experience a negative change in voice. The following are rec-
ommendations for the treatment of patients presenting with a voice
disorder who consume cannabis.
First, during an evaluation, gather information about fre-
quency and quantity of cannabis consumption (eg, joint-years) in ad-
dition to delivery method (eg, smoking, vaporizer, or dabbing). Re-
quest the type of cannabis product being consumed (eg, cannabis
flower, hash, or extract) to appreciate exposure to pharmacologi-
cally active constituents. Strain-specific cannabinoid levels may be
found online, and states with legalized cannabis require display of
THC and CBD levels on packaging.
Second, complete a visual examination in patients with voice
disorders who inhale cannabis by using laryngoscopy, possibly with
stroboscopy, to assess laryngeal structures and vocal fold vibration.70
Practitioners can expect vocal fold erythema and edema.49,50 Pul-
monary function testing may be warranted to evaluate the contri-
bution of lung function to dysphonia.
Third, during treatment, provide education on methods of con-
suming cannabis and their different associations with voice disor-
ders. On the basis of temperature and humidity profiles, nonin-
haled consumption methods, such as edibles, tinctures, or salves,
are preferred for vocal health over inhaled ones. Noncombustion in-
halation by vaporizing is preferred over combustion by smoking.
Identify strategies to optimize vocal health (eg, use of nebulizers or
humidifiers). Discuss the compounding effect when smoking
cannabis with tobacco, including risk of pulmonary diseases and
cancer.
E7
 Clinical Review & Education Review Cannabis Inhalation and Voice Disorders

Fourth, dysphonia can occur from vibratory changes with al-

terations in vocal fold viscoelastic properties. Edema is likely if re-
spiratory effects are indicative of laryngeal effects from exposure
to degradation byproducts with cannabis smoking.71 Educate pa-
tients that substantial cannabis smoking may be associated with poor
lung function and potentially with problems with expiratory force
generation for voice. Teach strategies to optimize voice in the set-
ting of lung congestion and possible vocal fold edema.
Limitations
This study has some limitations that merit consideration. Only studies
written in English were selected. The limited date range may have led
toomissionofresults,althoughincreasedpotencyofcannabisovertime
may render older studies less relevant to current consumers.24 Incon-
sistencies in how cannabis consumption was measured and varying
agesofparticipantsconfoundanalysisandpreventextrapolationoffre-
quency or intensity effects.
Conclusions
Recent advances in the legal status of cannabis have outpaced
medical research, in particular on voice disorders. In this system-
atic review, cannabis inhalation was associated with darkened
vocal folds on laryngoscopy and with structural and functional
changes in the airways in part because of degradation byproducts
in a dose-response relationship. Respiratory symptoms
and changes improved with cessation of cannabis consumption
or changing to vaporizing methods. The findings suggest that
practitioners managing voice disorders should gather details
about patterns of cannabis consumption and educate consumers
about negative changes with inhalation. Further research appears
to be needed on cannabis inhalation and its association with
the phonatory system’s health and function, as well as its possible
therapeutic applications.

ARTICLE INFORMATION
Accepted for Publication: June 7, 2019.
Published Online: August 8, 2019.
doi:10.1001/jamaoto.2019.1986
Author Contributions: Dr Ziegler and Mr
Meehan-Atrash had full access to all the data in the
study and take responsibility for the integrity of the
data and the accuracy of the data analysis.
Concept and design: All authors.
Acquisition, analysis, or interpretation of data:
All authors.
Drafting of the manuscript: All authors.
Critical revision of the manuscript for important
intellectual content: All authors.
Statistical analysis: All authors.
Administrative, technical, or material support:
Meehan-Atrash, Ziegler.
Supervision: Ziegler.
Conflict of Interest Disclosures: Mr
Meehan-Atrash reported receiving personal fees
from Farmhouse Tomatoes, a medical marijuana
company outside the submitted work. Dr Ziegler
reported receiving personal fees from Laryngology
Education Foundation during the conduct of the
study. No other disclosures were reported.
Funding/Support: This research was supported by
funds from the Department of Otolaryngology–
Head & Neck Surgery, Oregon Health & Science
University, Portland.
Role of the Funder/Sponsor: The funding source
had no role in the design and conduct of the study;
collection, management, analysis, and
interpretation of the data; preparation, review, or
approval of the manuscript; and decision to submit
the manuscript for publication.
Meeting Presentation: This paper was presented
as a poster at the Fall Voice Conference Meeting of
the Laryngology Educational Foundation; October
25-27, 2018; Seattle, Washington.
Additional Contributions: Laura Zeigen, MA, MLIS,
MPH, AHIP, assistant professor and librarian at
Oregon Health & Science University, Portland,
assisted with queries to identify articles and was
not compensated by the authors.
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