C H A P T E R
e8
Cannabis and Oral Health:
Deleterious Effects on Periodontitis
and Dental Implants
G. Nogueira-Filho
School of Health Sciences, University Salvador, Laureate International Universities,
Salvador, Bahia, Brazil
SUMMARY POINTS
• Cannabis smoke decreases bone filling around
titanium implants.
• Cannabis smoke impairs cancellous bone formation.
• Cannabis does not affect the cortical bone around
the implants.
• Cannabis smoke increases bone loss in teeth with
induced periodontitis.
• Cannabis smoke had no effect on bone physiology
in periodontally healthy teeth.
• The deleterious impact of Cannabis on bone
healing represents a new concern for dental
implants success/failure.
• There is a lack of evidence to prove the role of
Cannabis as an etiologic risk factor for periodontitis.
• Further investigations are necessary to determine
whether smoking Cannabis can be considered a
real threat to oral health.
KEY FA C T S
• Cannabis sativa can enhance an established
inflammatory response in periodontitis sites
• Cannabis sativa can enhance bone loss around dental
implants
• Cannabis sativa is not able to initiate disease at the
gingival and bone levels
LIST OF ABBREVIATIONS
CB1
Cannabinoid receptor-1
CB2
Cannabinoid receptors-2
CBD
Cannabidiol
D9-THC D9-tetrahydrocannabinol
IFNg
Interferon gamma
IL-1
Interleukin 1
IL-6
Interleukin 6
IL-10
Interleukin 10
NK cells Natural killer cells
Th1
T helper 1 lymphocyte
Th2
T helper 2 lymphocyte
THC
Tetrahydrocannabinol
TNFa
Tumor necrosis factor alpha
INTRODUCTION
Cannabis sativa (marijuana) is a plant that contains more
than 60 types of cannabinoids produced by small glands
on its leaf surface (Grotenhermen, 2004). Cannabis and its
cannabinoids can affect the immunological human functions (Peeke, Jones, & Stone, 1976). Cannabinoids seem to
attenuate the production of some inflammatory mediators such as interferon-g (IFNg), tumor necrosis factor-a
(TNFa), interleukin (IL)-1, IL-6, and IL-10 (Klein, 2005;
Massi, Vaccani, & Parolaro, 2006). Cannabinoids activate specific cell-surface cannabinoid receptors-1 and
-2 (CB1 and CB2, respectively), which are normally
engaged by a family of endogenous ligands so-called
Handbook of Cannabis and Related Pathologies. http://dx.doi.org/10.1016/B978-0-12-800756-3.00057-0
Copyright © 2017 Elsevier Inc. All rights reserved.
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Studies
the ­endocannabinoids (Do, McKallip, Nagarkatti, &
Nagarkatti, 2004). Compounds that bind these receptors
induce cannabimimetic responses in vivo and in vitro. Indeed, recent evidence indicates that ­cannabinoids might
influence vascular inflammatory diseases in several
ways such mediating vasodilatation particularly in lipopolysaccharide (LPS) induced infectious diseases (Grotenhermen, 2004). The cannabinoids can also reduce the
immune response, and impair the body defense against
viral, bacterial, and protozoa’s infections (Do et al., 2004).
Experimental models have been used for host response
evaluation in cultures of cells exposed to tetrahydrocannabinol (THC), and in human populations of declared
consumers of cannabis. These studies suggest that the
cannabinoids can affect the resistance of the host by modifying the primary and secondary immune system, especially the function of lymphocyte T and B, as well as the
NK cells and macrophages (Klein, 2005). Moreover, cannabinoids can act as immunomodulators by modifying the
production and function of cytokines in the acute phase
of the inflammatory process in the phases T helper 1 (Th1)
and T helper 2 (Th2). Animal and cell experiments have
demonstrated that THC exerts complex effects on cellular and humoral immunity. THC was shown to modulate
the immune response of T lymphocytes. It suppressed the
proliferation of and Th2 cytokines (Grotenhermen, 2004).
Cannabinoids can influence vascular inflammatory
diseases (Powles, te Poele, & Shamash, 2005) in several ways, such as mediating vasodilatation, particularly in LPS-induced diseases. Studies (Davies, Sornberger, & Huber, 1979; Idris, van’t Hof, & Greig, 2005;
Ofek et al., 2006) have also indicated the association
between bone loss and the use of cannabis. Considering bone metabolism, the suspect of cannabis effect was
confirmed by molecular studies that demonstrated a
negative impact on bone physiology by cannabinoids
(Grotenhermen, 2004; Klein, 2005; Tam, Ofek, & Fride, 2006).
Nakajima, Furuichi, and Biswas (2006) suggested a
possible role of cannabinoids in periodontitis by reporting expression of cannabinoid receptors (CB1 and CB2)
in periodontal tissues, followed by an increase in anandamide, an agonist of the cannabinoid receptor derived
from arachidonic acid. Many oral problems have been associated with the use of cannabis, including xerostomia,
with predisposition to dental caries and periodontitis,
severe gingivitis, oral mucosal disease, abnormal stress
response on administration of adrenalin-containing local anesthetics, leukoedema, and increased prevalence
of opportunistic microorganisms such as Candida albicans (Darling, Arendorf, & Coldrey, 1990; Versteeg, Slot,
van der Velden, & van der Weijden, 2008; Veitz-Keenan
& Spivakovsky, 2011; Nogueira-Filho et al., 2011; Kayal,
Elias, Alharthi, Demyati, & Mandurah, 2014).
Considering the apparent lack of scientific information regarding the effects of cannabis on oral bones, and
its impact in oral inflammation, our research group has
developed an animal model to study second hand cannabis smoke in rats (Fig. e8.1). So far, we have summarized
the main findings of two studies published recently in
dental journals (Nogueira-Filho, Cadide, & Rosa, 2008;
Nogueira-Filho et al., 2011) that reflect our impressions
about the possible relationship between cannabis and
the health of oral bones around teeth, and also on the
bones around endosseous titanium implants.
STUDIES
STUDY 1. Cannabis sativa smoke inhalation decreases
bone filling around titanium implants: a histomorphometric
study in rats (Nogueira-Filho et al., 2008)
In this first study, we aimed to investigate if second
hand cannabis smoke could impair bone formation and
repair around prototypes of dental implants to be inserted in rat tibia (Figs. e8.2 and e8.3).
Thirty Wistar rats were used in this study. After anesthesia, the tibiae surface was exposed, and one screwshaped titanium implant was placed bilaterally. The
animals were randomly assigned to one of the following
groups: CTRL (control; n = 15), and MSI (cannabis smoke
inhalation 8 min/day; n = 15), as illustrated in Fig. e8.1.
Urine samples were obtained to detect the presence of
THC for both groups. After 60 days, the animals were
killed. The degree of bone-to-implant contact and the
bone area within the limits of the threads of the implant
were measured in the cortical (zone A) and cancellous
bone (zone B). The experiment finished with 23 animals,
instead of 30 (CTRL/n = 15, and MSI/n = 8), as seven rats
died during the experiment because of respiratory failure provoked by intermittent cannabis smoke inhalation.
THC was detected in urine samples from all animals from
MSI group (n = 8). Negative THC detection was found
in all samples from control animals. Also, according to
the Brazilian Research Protocol for Illegal Drugs, all human researchers that worked directly with the cannabis
smoke experiments had also their urine checked. All their
samples were negative to THC (Table e8.1), confirming
the effectiveness of their personal protective equipment
used during cannabis handling and smoke exposure.
This study demonstrated that cannabis smoke inhalation had a deleterious impact on cancellous bone healing
around titanium implants by reducing bone filling and
bone-to-implant contact inside the implant threads, while
no effect was observed in the cortical bone (Figs. e8.2
and e8.3). The negative effects of cigarette smoking on
periodontitis and around titanium implants have been
demonstrated by the authors (Nogueira-Filho, Froes
Neto, & Casati, 2004; Nogueira-Filho, Rosa, Cesar-Neto,
Tunes, & Tunes, 2007), where cigarette smoking seems
to reduce bone capacity to formation and/or increasing
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e8. Cannabis and Oral Health: Deleterious Effects on Periodontitis and Dental Implants
FIGURE e8.1 Illustrations of the cannabis smoke-generating apparatus (A), before (B) and during smoke exposure (C). (A) Depiction of
the cannabis smoke apparatus; (B) animals inside the apparatus before cannabis smoke exposure; (C) animals inside the apparatus during smoke
exposure. This figure shows an illustration of the cannabis smoke apparatus (A) and the actual smoke exposure (B and C) according to the cannabis smoke exposure protocol.
FIGURE e8.2 Photomicrographs illustrating bone healing in the implant surface (Toluidine blue; original magnification = 4×). These
photomicrographs (4×) correspond to histological sections from titanium implants inserted in the rat tibias. (A) Represents control rats, whereas
(B) represents cannabis-exposed rats. The black zone (a) corresponds to the titanium implant screw; the inner pink zone (b) corresponds to newly
formed bone in direct contact to the implant surface while the outer pink zone (c) corresponds to original bone. Source: Data are from Nogueira-Filho
et al. (2008).
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Studies
FIGURE e8.3 Photomicrographs illustrating bone healing in the implant surface (Toluidine blue; original magnification = 100×). These
photomicrographs (100×) correspond to histological sections from titanium implants inserted in the rat tibias. (A) Represents control rats, whereas
(B) represents cannabis-exposed rats. The black zone (a) corresponds to the titanium implant screw; the blue zone (b) corresponds to newly formed
bone in direct contact to the thread surface of the implant, while the empty zone (c) corresponds to lack of bone-to-implant contact, that is, no
direct bone formation on the implant surface. Source: Data are from Nogueira-Filho et al. (2008).
TABLE e8.1 Tetrahydrocannabinol (THC) Detection in Urine Samples
Animals
1
2
3
4
5
6
7
8
9
10
11
12
13
14
15
CTRL
−
−
−
−
−
−
−
−
−
−
−
−
−
−
−
MSI
+
+
+
+
+
+
+
+
RES
1
2
3
4
−
−
−
−
a
This table shows THC presence (+) or absence (–) in urine collected from rats exposed to cannabis smoke (MSI), control rats (CTRL), and human researchers (RES)
that worked with the cannabis apparatus (as shown in Fig. e8.1).
a
Seven animals from MSI died during experiment due respiratory complications.
Data are from Nogueira-Filho et al. (2008).
resorption. Despite the limitations of the present study, it
is the first one, to our knowledge, that demonstrates the
negative impact of Cannabis sativa smoke on bone healing around titanium implants.
According to Tam et al. (2006), bone mass and shape
are determined by continuous remodeling consisting
of the concerted and balanced action of osteoclasts (the
bone resorbing cells), and osteoblasts (the bone forming
cells). Firstly, immune cells express endocannabinoids,
and cannabinoid receptors (CB1 and CB2) at the surface
of immune cells are activated after infection or immune
stimulation. The second general principle is that the main
immune targets of cannabinoid-based drugs involve the
suppression of cytokines and cell-mediated immunity,
through cannabinoid receptor-dependent and -independent mechanisms. The results of the present study clearly
demonstrated that cannabis smoke could decrease bone
mass around titanium implants in the cancellous zone.
As a matter of fact, to explain such phenomenon, some
observations might be further addressed considering the
CB1/CB2 receptor system of the cannabinoids.
Bone is densely innervated by sympathetic fibers
(Mach, Rogers, & Sabino, 2002). These fibers release norepinephrine, thus potently mediating central signals that
restrain bone formation, and stimulate bone resorption
(Schlicker & Kathmann, 2001). Because CB1 is expressed
in such nerve fibers elsewhere, its presence in bone sympathetic nerve fibers was further explored, indicating
also the presence of CB1 receptors in sympathetic fibers
that innervate the cancellous bone (Elefteriou, Ahn, &
Takeda, 2005).
On the other hand, CB2 receptors are located principally in immune cells, among them leukocytes, in
the spleen, and tonsils. Immune cells also express CB1
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e8. Cannabis and Oral Health: Deleterious Effects on Periodontitis and Dental Implants
receptors, but there is markedly more mRNA for CB2
than CB1 receptors in the immune system. One of the
functions of CB receptors in the immune system is
modulation of cytokine release. Activation of the CB1
receptor produces cannabis-like effects on psyche and
circulation, while activation of the CB2 receptor does not.
CB2 is expressed in the vast majority of hematopoietic
cells, including macrophages, and attenuates immune
responses. CB2 is expressed in osteoblasts, osteocytes,
and osteoclasts. It was found that osteoclasts, cells derived from the monocyte-macrophage lineage, have high
levels of CB2 mRNA (Ofek et al., 2006). Specific cannabinoids as the CB2 are also characterized by increased
activity of osteoblasts (bone-forming cells), increased osteoclast (bone-resorbing cell) numbers, and a markedly
decreased number of osteoblast precursors.
Our results were not able to present any disturbance
in the cortical bone around the implants placed in the
rats that inhaled the cannabis smoke. Interestingly, this
phenomenon could be explained by the presence of a
CB2-specific agonist that does not have any psychotropic
effects enhancing endocortical osteoblast number and
activity. Cannabis smoke inhalation somehow seems to
impair the healing of the cancellous bone, probably because of a THC effect in inhibiting CB2 expression on
osteoblasts and, consequently, reducing bone formation.
In the same way, the reduced bone-to-implant contact
values in the cannabis group may also suggest the occurrence of a restraining in the osteoclastogenesis, apparently because of the inhibition of the proliferation of osteoclast precursors, and receptor activator of NF-kB ligand
expression in bone marrow-derived osteoblasts/stromal
cells (Nakajima et al., 2006). Endocannabinoids could
regulate the periodontal inflammation through NF-kB
pathway inhibition. The endocannabinoid ­system seems
to participate in bone physiology by regulating bone
mass, bone loss, and osteoclast activity by signaling via
the peripheral CB2 expressed in bone, and its effect decreased the bone healing around the implants in the experimental rats from cannabis group (Idris et al., 2005).
As long as it is well established that titanium implant
success is a reality, and only a few situations, such as
cigarette smoking, may cause implant failure, this study
was a hallmark as the first in the literature to raise the
concern about the consumption of cannabis as a possible
risk factor in order to explain some of dental implant
failures in patients that not always inform, during anamnesis, that they are marijuana consumers. Nevertheless, further epidemiological and molecular studies are
mandatory to confirm such suspect.
STUDY 2. Marijuana smoke inhalation increases bone
loss during ligature-induced periodontitis (Nogueira-Filho
et al., 2011)
In this second study, we aimed to investigate if second
hand cannabis smoke could increase bone inflammation
around teeth with induced periodontal inflammation, in
a rat model.
30 male Wistar rats were used in the study. A ligature
was placed around one of the mandible first molars (ligated teeth) of each animal, and they were then randomly
assigned to one of two groups: CTRL (control; n = 15), or
MSI (marijuana smoke inhalation for 8 min/day; n = 15),
as illustrated in Fig. e8.1. Urine samples were obtained
to detect the presence of THC. After 30 days, the animals
were killed, and decalcified sections of the tooth furcation area were obtained and evaluated according to the
following histometric parameters: bone area, bone density, and bone loss.
Seven rats in the MSI group died during the experimental period, probably because of respiratory failure
provoked by intermittent cannabis smoke inhalation;
however, no further investigations were performed to
confirm the cause of death. At the end of the 30 days of
cannabis inhalation, the remaining animals from the MSI
group presented abnormal behavior, as noted by erratic
movements in the cage, and excessive food ingestion.
The teeth ligatures that promoted periodontitis were
kept in place in all 23 animals that completed the experimental period, and served as a retention device for oral
microorganisms.
This study demonstrated that cannabis smoke inhalation increased bone loss in the furcation area of teeth
with induced periodontitis in rats, whereas no effect was
observed in periodontally healthy sites, confirmed by
the histomorphometric analysis that showed the highest values of bone loss into the furcation area from cannabis-exposed teeth (Fig. e8.4). Despite the studies by
Davies et al. (1979) on the effect of marijuana inhalation
on alveolar macrophages, by the use of a smoke exposure chamber, to the best of our knowledge, this is the
first study evaluating the influence of cannabis smoke
on healthy periodontal tissues, and during experimental
periodontitis.
Though our results and the biologic plausibility
that cannabis use could be considered a possible risk
factor for periodontitis, some limitations of the present study have to be emphasized. Some animals from
the cannabis group probably died because of respiratory difficulties because the smoke that was produced
looked very dense and dusty, and may not be comparable to the doses inhaled by human cannabis consumers. Also, regardless of our interesting results,
contradictory findings may be observed in other studies. Conversely, Napimoga, Benatti, and Lima (2009)
demonstrated experimentally that the administration
of cannabidiol (CBD), a cannabinoid component from
Cannabis that does not induce psychotomimetic effects,
and possess antiinflammatory properties, significantly
inhibited bone loss in experimental periodontitis in rats.
The study by Napimoga et al. (2009) suggests that such
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Final considerations
FIGURE e8.4 Photomicrographs illustrating the furcation region of a rat molar showing no bone loss in the control group with no cannabis
smoke exposure (hematoxylin and eosin; magnification = 10×). These photomicrographs correspond to histological sections from the rat teeth.
(A) Represents control rats, whereas (B) represents cannabis-exposed rats. For (A) and (B), the zone (a) corresponds to the tooth root, and zone
(b) corresponds to the furcation area filled with original bone. For (B), the zone (c) corresponds to furcation bone loss due the cannabis smoke
exposure. Source: Data are from Nogueira-Filho et al. (2011).
cannabis antiinflammatory effect might be related to
drug-induced reduction of bone-related molecules, as
receptor activator of NF-kB and receptor activator of
NF-kB ligand expression, neutrophil infiltration, and
cytokine production at gingival tissues.
Although both studies (Napimoga et al., 2009; NogueiraFilho et al., 2011) used the same experimental model
(ligature-induced periodontitis in rats), a direct comparison between the studies has to be taken with caution.
Napimoga et al. (2009) tested just cannabidiol, one of
the compounds of Cannabis smoke, whereas the study
by Nogueira-Filho et al. (2011) evaluated whole Cannabis smoke inhalation. Interestingly, cannabis leaves, like
tobacco leaves, contain more than 400 compounds, but
Cannabis presents at least 60 cannabinoids. The noncannabinoid constituents are similar to tobacco (except for
nicotine), which carry systemic health risks, and have
histopathologic effects similar to those of tobacco smoke.
Realistically, in the study by Napimoga et al. (2009) only
cannabidiol was administered via intraperitoneal injections in the rats; whereas the animals in the study by
Nogueira-Filho et al. (2011) inhaled the cannabis smoke
itself. These methodological differences may explain, at
least in part, the contradictory results of these two interesting studies.
Two relevant clinical studies have reported the effects of cannabis usage on periodontal tissues. In a
prospective cohort study, Thomson, Poulton, and
Broadbent (2008) found Cannabis smoking to be an
independent risk factor for periodontal disease. Contradictorily, López and Baelum (2009) found no evidence associating the use of cannabis with periodontal
diseases. The human populations of each investigation
may be considered the most important difference, when
comparing both studies. The study by Thomson et al.
(2008) evaluated only adult patients (∼32 years old);
however, López and Baelum (2009) evaluated younger
patients (∼12–21 years old). Notwithstanding this, it is
well recognized that in such clinical studies it is difficult to control the frequency, amount, duration, and
mode of administration of cannabis in all individuals
included in epidemiological evaluations. Personal risk
factors, including age, oral hygiene, general health,
concurrent tobacco smoking, and multidrug use, may
also act as confounding factors, making even more difficult the identification of the specific influence of Cannabis on periodontitis.
FINAL CONSIDERATIONS
Our studies propose a methodology widely used to
evaluate the influence of cigarette smoke on living tissues, in order to study the impact of Cannabis smoke on
ligature-induced periodontitis, and on endosseous implants. Cigarette and Cannabis smoke are quite similar
regarding composition, which may result in similar biologic effects. Cigarette smoking can reduce bone capacity
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e8. Cannabis and Oral Health: Deleterious Effects on Periodontitis and Dental Implants
of formation or increase its resorption. Similarly, the
present results demonstrate that Cannabis smoke might
also alter bone pathophysiologic patterns. Cannabinoids
may suppress important biologic pathways related to inflammatory processes, whereas nicotine, a key tobacco
constituent, promotes these pathways. However, the
biologic pathway by which Cannabis smoke exerts its effects on periodontal tissues and bone around dental implants is still not totally understood.
Because the healthy groups did not present changes
in the bone levels, the greater bone loss found in the Cannabis groups for periodontitis sites, and around titanium
implants, might be probably related to impaired immune
function during the process of bone repair, or even the activation of specific receptors that might increase bone destruction. In this regard, some speculation has arisen about
the endocannabinoid system that seems to play a role in
the regulation of bone metabolism. The suspicion of a Cannabis effect on bone metabolism was confirmed by some
molecular studies that demonstrated a negative impact by
cannabinoids on bone physiology. Mice lacking either of
the cannabinoid receptors CB1 or CB2 have abnormal bone
phenotypes because cannabinoid receptor agonists and inverse agonists reduce bone loss by presenting direct effects
on both bone-resorbing cells (osteoclasts) and bone-forming
cells (osteoblasts) in vitro. Nevertheless, conflicting results
have been reported with regard to the effects of Cannabis
on the regulation of bone mass via bone resorption and osteoclast function. THC has also demonstrated a direct impact on immune cell activity, leading to immunosuppressive effect on macrophages, natural killer cells, and T and
B-lymphocytes.
Undoubtedly, it is wise to consider the fact that many
individuals have or will have contact with Cannabis as a
recreational drug, or as a daily basis usage. The question
remains as to how far this Cannabis smoking habit may
disrupt the bone homeostasis in the oral cavity.
MINI-DICTIONARY
Bone loss Bone loss is the breakdown of bone through a process
also called bone resorption, in which bone volume and bone
density are decreased physiologically or because of a disease.
Bone resorption Bone resorption is the destruction of bone tissues
that promotes bone loss, that is, a decrease in bone mass and bone
density.
Furcation region Furcation region of a tooth corresponds to the
area filled by bone in between the roots. It is generally found in
multiradicular teeth in the oral cavity.
Hematoxylin and eosin (H&E) stain H&E is a common
histological staining method for tissues, in which the cell nuclei
are stained in a deep blue with hematoxylin, while the cell
cytoplasm is stained in a pink color after the counterstaining with
eosin.
Periodontal disease Periodontal disease is an inflammation
of gingiva and oral bones around teeth. It is called gingivitis
when only the gingiva is affected by inflammation, whereas
periodontitis involves destruction of alveolar-supporting bone
around teeth.
Trabecular bone Trabecular bone is a synonymous with
the cancellous bone. It is one of two types of bone tissue in
vertebrates.
Xerostomia This is a condition in which there is an extreme decrease
of salivary flow in the oral cavity, promoting mouth dryness. It is
usually due to physiological and/or pathological decrease of saliva
production by the salivary glands present in the oral cavity.
Acknowledgments
The authors thank The National Council for Scientific and Technological Development (CNPq), a foundation linked to the Ministry of
Science and Technology (MCT), for supporting this research (#grant
308114/2004-3), The Federal Police Department of Brazil, Public Security Secretary and The Health State Secretary authorities for providing
legal use of Cannabis sativa samples in experimental protocols.
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