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1) Background: The healing properties of cannabidiol (CBD) have been known for centuries. In this study, we aimed to evaluate the efficiency of the myorelaxant effect of CBD after the transdermal application in patients with myofascial pain. (2) Methods: The Polish version of the Research Diagnostic Criteria for Temporomandibular Disorders (RDC/TMD Ia and Ib) was used. A total of 60 patients were enrolled in the study and were randomly divided into two groups: Group1 and Group2. The average age in Group1 was 23.2 years (SD) = 1.6 years) and in Group2, it was 22.6 years (SD = 1.86). This was a parallel and double-blind trial. Group1 received CBD formulation, whereas Group2 received placebo formulation for topical use. The masseter muscle activity was measured on days 0 and 14, with surface electromyography (sEMG) (Neurobit Optima 4, Neurobit System, Gdynia, Poland). Pain intensity in VAS (Visual Analogue Scale) was measured on days 0 and 14. (3) Results: in Group1, the sEMG masseter activity significantly decreased (11% in the right and 12.6% in the left masseter muscles). In Group2, the sEMG masseter activity was recorded as 0.23% in the right and 3.3% in the left masseter muscles. Pain intensity in VAS scale was significantly decreased in Group1: 70.2% compared to Group2: 9.81% reduction. Patients were asked to apply formulation twice a day for a period of 14 days. (4) Conclusion: The application of CBD formulation over masseter muscle reduced the activity of masseter muscles and improved the condition of masticatory muscles in patients with myofascial pain.
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Journal of
Clinical Medicine
Article
Myorelaxant Eect of Transdermal Cannabidiol
Application in Patients with TMD: A Randomized,
Double-Blind Trial
Aleksandra Nitecka-Buchta 1, * , Anna Nowak-Wachol 1, Kacper Wachol 1,
Karolina Walczy´nska-Dragon 1, Paweł Olczyk 2, Olgierd Batoryna 2, Wojciech Kempa 3and
Stefan Baron 1
1Department of Temporomandibular Disorders, Medical University of Silesia in Katowice, 2 Traugutta sq,
41-800 Zabrze, Poland; nowak.anna@med.sum.edu.pl (A.N.-W.); kacper.wachol@med.sum.edu.pl (K.W.);
karolina.dragon@sum.edu.pl (K.W.-D.); sbaron@sum.edu.pl (S.B.)
2Department of Community Pharmacy, Medical University of Silesia, 41-200 Sosnowiec, Poland;
polczyk@sum.edu.pl (P.O.); obatoryna@sum.edu.pl (O.B.)
3Faculty of Applied Mathematics, Silesian University of Technology, 44-100 Gliwice, Poland;
wojciech.kempa@polsl.pl
*Correspondence: aleksandra.nitecka@sum.edu.pl; Tel.: +48-6018-990-69
Received: 5 October 2019; Accepted: 4 November 2019; Published: 6 November 2019


Abstract:
(1) Background: The healing properties of cannabidiol (CBD) have been known for
centuries. In this study, we aimed to evaluate the eciency of the myorelaxant eect of CBD after
the transdermal application in patients with myofascial pain. (2) Methods: The Polish version of
the Research Diagnostic Criteria for Temporomandibular Disorders (RDC/TMD Ia and Ib) was used.
A total of 60 patients were enrolled in the study and were randomly divided into two groups: Group1
and Group2. The average age in Group1 was 23.2 years (SD) =1.6 years) and in Group2, it was
22.6 years (SD =1.86). This was a parallel and double-blind trial. Group1 received CBD formulation,
whereas Group2 received placebo formulation for topical use. The masseter muscle activity was
measured on days 0 and 14, with surface electromyography (sEMG) (Neurobit Optima 4, Neurobit
System, Gdynia, Poland). Pain intensity in VAS (Visual Analogue Scale) was measured on days 0 and
14. (3) Results: in Group1, the sEMG masseter activity significantly decreased (11% in the right and
12.6% in the left masseter muscles). In Group2, the sEMG masseter activity was recorded as 0.23% in
the right and 3.3% in the left masseter muscles. Pain intensity in VAS scale was significantly decreased
in Group1: 70.2% compared to Group2: 9.81% reduction. Patients were asked to apply formulation
twice a day for a period of 14 days. (4) Conclusion: The application of CBD formulation over masseter
muscle reduced the activity of masseter muscles and improved the condition of masticatory muscles
in patients with myofascial pain.
Keywords: cannabidiol; CBD; myofascial Pain; TMD; bruxism; EMG; masseter muscle
1. Introduction
Nowadays, dental practitioners are more obliged to treat patients suering from myofascial pain
(MFP). The main syndrome, which forces patients to search for medical help, is face and neck pain,
headache and pain in the ear. Bruxism, the common sleep disorder and parafunctional activity of
the masticatory system, may be considered one of the major causes of tooth wear and masticatory
muscles MFP. Bruxism—determined by an increased activity of the limbic system, together with the
modification of excitability of the neuromuscular spindles, leading to an increase in muscle contraction
strength, which persists despite the end of motor function—constitutes a risk factor for the development
J. Clin. Med. 2019,8, 1886; doi:10.3390/jcm8111886 www.mdpi.com/journal/jcm
J. Clin. Med. 2019,8, 1886 2 of 17
of temporomadibular disorders (TMD). Bruxism is a common phenomenon that can aect from 8
to even 31% of the population without significant dierences in relation to sex. Depending on the
time of occurrence, we can distinguish awake bruxism (AB) and sleep bruxism (SB) [
1
]. AB is a
masticatory muscle activity during wakefulness that is characterized by repetitive or sustained tooth
contact and/or by bracing or thrusting of the mandible and is not a movement disorder in otherwise
healthy individuals [
2
]. SB is a masticatory muscle activity during sleep that is characterized as
rhythmic (phasic) or non-rhythmic (tonic) and is not a movement disorder or a sleep disorder in
otherwise healthy individuals [
2
]. In addition, bruxism in the waking state is referred to as “centric”,
characterized by vertical loading of teeth, while bruxism during sleep is referred to as “eccentric”
characterized by horizontal displacement of teeth and grinding during sleep. SB can occur in about 13%
of the adult population. In childhood, this adverse phenomenon has the highest frequency, 14–20%,
and this decreases with age, reaching 3% among older people [3].
Myofascial pain (MFP) within masseter muscles is a common disorder. Excessive muscle eort in
bruxers may develop muscle pain. The main syndrome of myofascial pain is a trigger point: a hard,
painful on compression, palpable, localized nodule. Myofascial pain is a symptom of muscle damage.
Energy crisis is the reason for the initial sarcomere contracture, that leads to increased metabolism and
local hypoxia, muscle damage and inflammatory mediators release. Contraction knots are formed, as
an eect of local injury, ischemia and fiber lock. The blood flow around and within the trigger point is
reduced. Current approaches for trigger point management are needling, injections and deep massage.
Recently, there has been a heated debate regarding the controversial issue on the legalization of
marijuana for medical purposes. The leaves of marijuana along with the blossoms and the fruiting
tips of hemp are rich in tetrahydrocannabinol (THC). Cannabis sativa L. is known to contain more
than 565 chemical compounds that belong to dierent groups, such as flavonoids, dihydrostilbens,
phenanthrenes and the most characteristic for this plant—cannabinoids, mainly psychoactive THC,
cannabidiol (CBD), and cannabinol (CBN) [
4
,
5
]. The above-mentioned constituents—occurring in
the number of 120 active, mainly represented by psychoactive
9-tetrahydrocannabinol (THC),
cannabidiol (CBD) and cannabinol (CBN)—belong to the C21 or C22 terpenophenolic group of
compounds synthesized by the alkylation of resorcinol with a monoterpene unit [
6
]. The content of
individual phytocanabinoids in the plant raw material depends on the growing conditions, geographical
location, plant processing methods and the plant variety or chemotype which automatically aects
the pharmacological eect of the cannabis extract [
7
]. Psychoactive eect of THC limits its use in
clinical practice.
Despite the multi-character nature, cannabis is widely regarded as constituting only one very
diverse species, C. sativa L. Within which we can distinguish three varieties: C. sativa,C. indica and C.
ruderalis (var. sativa, var. indica, and var. ruderalis, respectively) [
7
]. Botanical Nomenclature Cannabis
sativa L. [8]:
Kingdom: Plantae (plants)
Subkingdom: Tracheobionta (vascular plants)
Superdivision: Spermatophyta (seed plants)
Division: Magnoliophyta (flowering plants)
Class: Magnoliopsida (dicotyledons)
Subclass: Hamamelididae
Order: Urticales
Family: Cannabaceae
Genus: Cannabis
Species: sativa
Cannabis sativa L. is an annual plant belonging to the order Urticales, family Cannabaceae,
and genus Cannabis (hemp) [
9
]. The highest concentration of THC and CBD is in female cannabis
inflorescence [
9
]. Among the dierent species of cannabis, its use depends on the application and
J. Clin. Med. 2019,8, 1886 3 of 17
content of cannabinoids. Industrial varieties are cultivated for seeds in order to obtain oil and hemp
fiber (the content of THC is usually less than 1%) [
10
]. Polyunsaturated fatty acids are an essential
component of cannabis, mainly found in the oil obtained from industrial varieties. The polyunsaturated
fatty acids are mainly linoleic (omega-6) and linolenic (omega-3) acids, which are in the proportion
which is recommended for human dietary intake. In addition, cannabis contains all exogenous,
indispensable amino acids [
11
]. Varieties containing high content of THC are used in medicine.
This compound is capable of inhibiting cyclooxygenase enzyme, which blocks prostaglandin synthesis,
thereby alleviating the symptoms associated with inflammation [4,12].
CBD is an organic chemical compound belonging to the group of cannabinoids, which is present
in hemp [
13
]. Unlike its isomer, THC, CBD does not have a psychoactive eect, but it aects the
psychoactive induction pathway caused by the action of THC [
14
]. CBD possesses anti-inflammatory
and anti-nociceptive properties [1518].
According to a publication in 2017 by the National Academies of Sciences, Engineering and
Medicine Waschington DC, cannabis might be used to treat chronic pain in adult patients [
19
]. In a
systematic review conducted by the American Academy of Neurology regarding the ecacy and
safety of medical marijuana, the authors stated that cannabinoids are eective in reducing spasticity
and painful spasm in patients with multiple sclerosis [
20
]. According to Koppel, cannabinoids are
eective at reducing pain from 12–15 weeks up to 1 year of therapy [20].
In the human body, cannabinoids show their eect via two types of cannabinoid receptors:
CB
1
—found primarily in the central nervous system and CB
2
—which occurs circumferentially and
mainly in the immune system [
5
]. CB receptors belong to the family of G-protein coupled receptors,
physiologically activated by endocannabinoids, arachidonic acid amides and esters such as anandamide
and arachidonoylglycerol [
21
]. Both CB receptor subtypes lead to inhibition of adenylate cyclase and
thus to reduced formation of the intracellular messenger substance cyclic adenosine monophosphate
(cAMP). CB
1
receptors are activated by THC and CBD and are responsible for the local analgesic
eect [
22
]. The chemical structure of THC and CBD is slightly dierent, resulting in a dierent
mechanism of action (Figure 1). THC acts as an agonist of cannabinoid receptors and CBD acts as an
antagonist [
4
]. CBD was shown to enhance the role of THC in neuropathic pain model [
23
] and in
another study, it was found to antagonize the eects of THC [
24
]. The eect may be dose-dependent [
25
].
J. Clin. Med. 2019, 8, x FOR PEER REVIEW 3 of 17
component of cannabis, mainly found in the oil obtained from industrial varieties. The
polyunsaturated fatty acids are mainly linoleic (omega-6) and linolenic (omega-3) acids, which are in
the proportion which is recommended for human dietary intake. In addition, cannabis contains all
exogenous, indispensable amino acids [11]. Varieties containing high content of THC are used in
medicine. This compound is capable of inhibiting cyclooxygenase enzyme, which blocks
prostaglandin synthesis, thereby alleviating the symptoms associated with inflammation [4,12].
CBD is an organic chemical compound belonging to the group of cannabinoids, which is present
in hemp [13]. Unlike its isomer, THC, CBD does not have a psychoactive effect, but it affects the
psychoactive induction pathway caused by the action of THC [14]. CBD possesses anti-inflammatory
and anti-nociceptive properties [15–18].
According to a publication in 2017 by the National Academies of Sciences, Engineering and
Medicine Waschington DC, cannabis might be used to treat chronic pain in adult patients [19]. In a
systematic review conducted by the American Academy of Neurology regarding the efficacy and
safety of medical marijuana, the authors stated that cannabinoids are effective in reducing spasticity
and painful spasm in patients with multiple sclerosis [20]. According to Koppel, cannabinoids are
effective at reducing pain from 1215 weeks up to 1 year of therapy [20].
In the human body, cannabinoids show their effect via two types of cannabinoid receptors:
CB
1
—found primarily in the central nervous system and CB
2
which occurs circumferentially and
mainly in the immune system [5]. CB receptors belong to the family of G-protein coupled receptors,
physiologically activated by endocannabinoids, arachidonic acid amides and esters such as
anandamide and arachidonoylglycerol [21]. Both CB receptor subtypes lead to inhibition of adenylate
cyclase and thus to reduced formation of the intracellular messenger substance cyclic adenosine
monophosphate (cAMP). CB
1
receptors are activated by THC and CBD and are responsible for the
local analgesic effect [22]. The chemical structure of THC and CBD is slightly different, resulting in a
different mechanism of action (Figure 1.). THC acts as an agonist of cannabinoid receptors and CBD
acts as an antagonist [4]. CBD was shown to enhance the role of THC in neuropathic pain model [23]
and in another study, it was found to antagonize the effects of THC [24]. The effect may be dose-
dependent [25].
Figure 1. 2D 9-tetrahydrocannabinol structure and cannabidiol structure.
For the first time, cannabinoids are being used in medicine to treat pain [26]. The properties of
cannabis that might result in its therapeutic use are mood improvement, sedation, and muscle
relaxation [27]. There are already several cannabinoid-based drugs in the world used for therapeutic
purposes. Two are currently available in Canada: Nabilone (Cesamet®, Valeant Pharmaceuticals Inc,
Laval, Canada, CB1 cannabinoid receptor agonist, and Nabiksimole (Sativex®, Bayer Schering
Pharma, Leverkusen, Germany), an extract containing delta-9-THC and CBD. Another cannabinoid-
based drug available in the US is dronabinol (Marinol®, Abbott Laboratories, Chicago, IL, USA), a
synthetic delta-9-tetrahydrocannabinol. Nabilone is an oral drug approved by Health Canada for the
treatment of severe chemotherapy-induced nausea and vomiting. Dronabinol, also in oral form, has
also been approved for the treatment of severe chemotherapy-induced nausea and vomiting, as well
as weight loss associated with acquired immunodeficiency syndrome. Nabiksimole is in the form of
an aerosol for use on the oral mucosa, as an adjunct treatment to spasticity or neuropathic pain in
adult patients with multiple sclerosis and incurable cancer pain [28].
Figure 1. 2D 9-tetrahydrocannabinol structure and cannabidiol structure.
For the first time, cannabinoids are being used in medicine to treat pain [
26
]. The properties
of cannabis that might result in its therapeutic use are mood improvement, sedation, and muscle
relaxation [
27
]. There are already several cannabinoid-based drugs in the world used for therapeutic
purposes. Two are currently available in Canada: Nabilone (Cesamet
®
, Valeant Pharmaceuticals Inc.,
Laval, Canada, CB1 cannabinoid receptor agonist, and Nabiksimole (Sativex
®
, Bayer Schering Pharma,
Leverkusen, Germany), an extract containing delta-9-THC and CBD. Another cannabinoid-based
drug available in the US is dronabinol (Marinol
®
, Abbott Laboratories, Chicago, IL, USA), a synthetic
delta-9-tetrahydrocannabinol. Nabilone is an oral drug approved by Health Canada for the treatment
of severe chemotherapy-induced nausea and vomiting. Dronabinol, also in oral form, has also been
approved for the treatment of severe chemotherapy-induced nausea and vomiting, as well as weight
J. Clin. Med. 2019,8, 1886 4 of 17
loss associated with acquired immunodeficiency syndrome. Nabiksimole is in the form of an aerosol
for use on the oral mucosa, as an adjunct treatment to spasticity or neuropathic pain in adult patients
with multiple sclerosis and incurable cancer pain [28].
The activity of cannabinoids is associated with the modulation of adenylate cyclase and the
operation of ion channels—by blocking N-type calcium channels, THC decreases the release of
acetylcholine in the hippocampus and norepinephrine from sympathetic nerve terminals [
29
]. Thus,
acetylcholine is not available to bind to the postsynaptic receptors thereby causing muscle contraction.
This mechanism of action is interesting to various groups of researchers. The potential myorelaxant
activity of CBD has become the subject of this study.
2. Experimental Section
This is a parallel-group, double-arm, randomized, double-blind clinical trial conducted to assess
the myorelaxantand antinociceptive eect of CBD. A total of 60 patients were enrolled in this study and
were provided with CBD formulation for dermal application. The enrolled patients were referred to the
Department of Temporomandibular Disorders at the Medical University of Silesia in Katowice, Poland.
2.1. Study Participants
In this study, patients were randomly selected from a group of 87 patients attending the Department
of Temporomandibular Disorders, Medical University of Silesia in Zabrze, Poland. Patients (n=60)
were randomly divided into two groups by allowing them to pick up a number (even or odd) from the
container with formulation (Figure 2). The groups were structured as follows: experimental group
(Group1, n=30, which includes 18 females and 12 males) and control group (Group2, n=30, which
includes 15 females and 15 males) (Figure 3). The average age in Group1 was 23.2 years (SD =1.6) and in
Group2 was 22.6 years (SD =1.86) (Table 1). Patients were subjected to a preliminary qualification test,
which included dental examination, functional assessment of the stomatognathic system, subjective
anamnesis, and allergy test for CBD formulation. Patients and members of the study group (dentists,
who performed and collected the results of muscle activity using surface electromyography (sEMG)
were blinded for allocation and treatment.
Table 1. Structure of Group I and Group II main descriptive values.
Variables Group1 Group2
N60 30 30
Sex Female/male 18/12 15/15
Age 23.2 (SD =1.6) 22.6 (SD =1.86)
RDC/TMD Ia 9 13
Ib 21 17
The inclusion criteria were as follows:
1. Patients who agree to participate in the study
2. Patient’s age must be within 18 and 60 years
3. Good general health
4.
Temporomandibular disorder–positive as per the Polish version of the Research Diagnostic
Criteria for Temporomandibular Disorders (RDC/TMD) for group Ia and Ib [30].
5. Presence of all teeth (with the exception of third molars)
The exclusion criteria were as follows:
1. Cannabis formulation/placebo formulation allergy
2. Hypersensitivity to substances to be used in the study
J. Clin. Med. 2019,8, 1886 5 of 17
3. Skin wounds with skin surface discontinuation
4. Addiction to cannabis
5. Patients being treated with analgesic drugs and/or drugs that aect muscle function
6. Fixed or removable dental prosthesis
7. Disease or autoimmune disorder associated with generalized muscular tension
This study was approved by the Bioethical Committee of the Silesian Medical Chamber in
Katowice, Poland (number KNW/0022/KB1/7/19) and is retrospectively registered at ClinicalTrials.gov
(NCT03994640). This study was performed in accordance with the Declaration of Helsinki and the
International Conference on Harmonization: Guidelines for Good Clinical Practice. Patients received
verbal and written information describing the trial and gave their consent to participate in the study.
J. Clin. Med. 2019, 8, x FOR PEER REVIEW 5 of 17
Figure 2. Flow chart of the two arms consolidated standards of reporting trials (CONSORT)-
randomized study.
Figure 3. Distribution of gender in experimental and control groups.
Table 1. Structure of Group I and Group II main descriptive values.
Variables Group 1 Group 2
N 60 30 30
Sex Female/male 18/12 15/15
Age 23.2 (SD = 1.6) 22.6 (SD = 1.86)
RDC/TMD Ia 9 13
Ib 21 17
Figure 2.
Flow chart of the two arms consolidated standards of reporting trials
(CONSORT)-randomized study.
J. Clin. Med. 2019, 8, x FOR PEER REVIEW 5 of 17
Figure 2. Flow chart of the two arms consolidated standards of reporting trials (CONSORT)-
randomized study.
Figure 3. Distribution of gender in experimental and control groups.
Table 1. Structure of Group I and Group II main descriptive values.
Variables Group 1 Group 2
N 60 30 30
Sex Female/male 18/12 15/15
Age 23.2 (SD = 1.6) 22.6 (SD = 1.86)
RDC/TMD Ia 9 13
Ib 21 17
Figure 3. Distribution of gender in experimental and control groups.
J. Clin. Med. 2019,8, 1886 6 of 17
2.2. Study Protocol
This study followed the consolidated standards of reporting trials (CONSORT) statement and was
performed between 01.01.2018 and 01.01.2019 in the Department of Temporomandibular Disorders at
the Medical University of Silesia in Katowice, Poland.
The trial consisted of two main visits, preceded by screening:
(1)
Screening visit for study participation and inclusion.
(2) Baseline visit for sEMG test (baseline EMG I, VAS I) and random allocation to the group, receiving
a packaging with formulation (CBD or placebo) along with the instructions on how to use it.
(3)
First follow-up visit after 14 days of application (follow-up EMG II, VAS II).
Patients were examined by experienced dentists (AN, KW). Randomization was performed by
ANB, a dentist, who was not involved in follow-up visits. The sEMG tests were performed by KWD
on Day 0 and Day 14. KWD used the same paper templates to place electrodes in exactly the same
position on follow-up visits on Day 0 and Day 14, to achieve comparable results. She was not aware of
the patient’s group.
2.3. sEMG Measurements
Masseter muscle tension (
µ
V) at rest and in maximal contraction was measured in previously
determined points, with four-channel Neurobit Optima 4.0 (Neurobit Systems, Poland). Points were
repeatably marked on patients’ skin on baseline visit (EMG I) and on follow-up visit (EMG II) in the
region of masseter with a special paper template. Two dischargeable electrodes with a diameter of
10 mm were placed with conductor gel on each of the masseter muscle: near the origin, under the
zygomatic arch, and on the angle of the mandible, approximately 10 mm from each other. The location
of the electrodes was based on anatomical landmarks, palpated by the dental practitioner during the
examination of stomatognathic system. Patients were asked to perform an isometric contraction of the
masseter muscles to find the best place to fix the electrode.
The placement of the electrodes, as well as preparation of the skin, was consistent with SENIAM
guidelines: facial hair was shaved if necessary and cleaned with alcohol (Surface ElectroMyoGraphy
for the Non-Invasive Assessment of Muscles, www.seniam.org). Four Ag/AgCl adhesive electrodes,
diameter 30 mm (Sorimex, Toru´n, Poland), were applied bilaterally, directly on both the masseter
muscles (under the zygomatic arch and on the angle of the mandible) with an interelectrode distance
of 10 mm. Patients remained in a silent and calm room and were made to sit in an upright position
with feet on the floor and looking forward. The occlusal plane was parallel to the floor. Reference
electrodes were placed on the neck. The sEMG signal was amplified and digitized.
First, sEMG signals of the resting position (RP) of the mandible were recorded. It was done
without the teeth contact and the position of the mandible was maintained only by the force of gravity
and viscoelasticity of the stomatognathic system tissues. Patients were asked to slightly open the
mouth until the teeth of the upper and lower jaw were out of contact. Then, the sEMG records of RP
from right and left masseter muscles were recorded during a maximal voluntary isometric contraction
(MVIC) and was established as the reference value: the tests were repeated thrice for each muscle on
each side. The tests were separated by at least 1 min of rest. The mean values of sEMG (
µ
V) of the
masticatory muscles in mandible’s RP and in MVIC, obtained from Bioexplorer Neurobit (Neurobit
Optima for sEMG, Neurobit Systems, Gdynia, Poland were analyzed and normalized. Results were
analyzed with Statistica 13.1 (Stat Soft, Krakow, Poland).
2.4. Normalization of sEMG Values
Normalization of the data collected allows for the assessment of the level of activity of the masseter
muscle during RP as compared to the maximal activation capacity of the masseter muscle [
31
,
32
].
The data were normalized by dividing the values by the values of the MVIC. Reliability of the
normalized data was higher, compared to nonnormalized data [33,34].
J. Clin. Med. 2019,8, 1886 7 of 17
2.5. Topical Application of CBD or Placebo Formulation
Patients in Group1 were given CBD formulation, which was prepared according to the individual
recipes for testing purposes. Many dierent vehicles were tested in order to obtain the best features of
the CBD formulation. Cannabis oil and Charlotte’s Web Hemp Extract Oil Formula Olive Oil 30 mL
(A00674, product code 910.061 Stanley Brothers Boulder CO80301, cannabinoid content is given in
Table 2). In Hemp Extract Oil, the concentration of CBD was 7.3% (66.97 mg CBD/mL, 0.461 mg
CBD-A/mL, and 0.28 mg CBD-V/mL). The density of Hemp Extract Oil was 925 mg/mL. Assumptions
of maximum concentration and lightweight formulation were adopted. The formula was developed
on the basis of ointments, which is characterized by optimal water binding properties and ease of
oil-water emulsion formation.
Table 2.
Cannabinoid content in Charlotte’s Web Hemp Extract Oil Formula Olive Oil (according to
Stanley Brothers Boulder Certificate).
Parameter Concentration
Hemp Extract 70 mg/serving
Cannabinoids
THC 0.00 mg/mL
THC-A <0.0467 mg/mL
THC-V <0.0467 mg/mL
CBD 66.97 mg/mL
CBD-A 0.461 mg/mL
CBD-V 0.280 mg/mL
CBG 2.05 mg/mL
CBG-A <0.0467 mg/mL
CBN <0.0467 mg/mL
CBC 3.74 mg/mL
2.5.1. Testing of Vehicle
With cholesterol as the vehicle, experimental ointment (for Group1) with 20% CBD oil was
prepared. The approximate content of CBD (CBD, CBD-A, and CBD-V) in this formulation was 1.46%.
The composition of cholesterol ointment (per 100 g) according to Polish Pharmacopoeia XI, on the
basis of which a formulation with CBD oil was prepared:
Cholesterol 3.0 g
Solid paran 15.0 g
Liquid paran 64.0 g
White vaseline 18.0 g
It was decided to develop a formulation based on cholesterol ointment due to the lack of
pharmaceutical incompatibility with the test hemp oil containing CBD. Cholesterol ointment is a type
of ocial pharmacopoeial medium used in pharmacy as an absorption medium, i.e., an emulsifying
active substance dissolved in a solvent, which is most often water. Cholesterol ointment can be used to
make various formulations as a vehicle, it can be also an independent preparation in an unprocessed
form. A large “amount of water”, defined as the amount of water in grams that 100 g of substrate
permanently binds at 20
C of 120 for the substrate used, allows to emulsify a large amount of water and
aqueous solutions. The presence of water in the formulation will reduce the feeling of greasiness—the
preparation will have a lighter consistency and will allow the introduction of any additional active
substances or water-soluble preservatives into the drug. The discussed medium can be applied to
J. Clin. Med. 2019,8, 1886 8 of 17
thermally and mechanically damaged skin, in atopic dermatitis and after long-term treatment with
steroid ointments, so any pathological changes at the application site will not be a restriction on the
use of the preparation. All ingredients are safe for the skin and do not cause irritation. There are also
no specific contraindications for the use of this ointment base.
2.5.2. Preparation of CBD Formulation
Oleum CBD 2.0 g (20% CBD oil)
Aqua purificata 3.0 g
Ung. Cholesterol 5.0 g
Patients in Group2 were given control formulation, based on cholesterol as the vehicle but without
CBD oil. The following is the composition of control formulation:
2.5.3. Preparation of Control Formulation
Aqua purificata 3.0 g
Ung. Cholesterol 5.0 g
The ointments had the same consistency and color, they were packed in the same containers,
which made it impossible to distinguish the formulation with CBD oil from placebo.
In both groups, the formulation was intended for topical use to be applied on the skin surface of
the masseter muscle, at the right and left side. Containers with CBD formulation were marked with
even and odd digits for the appropriate group to allocate patient in one of the two groups. In addition
to patients, doctors did not know the identity of the formulation. First, patients were asked to perform
an allergy test by applying a small amount of the formulation (placebo or CBD) on the skin of the
forearm 24 h before therapy. In the case of swelling, itching, or redness on skin, the patients were asked
to quit therapy.
Each patient had been taught on the procedure to apply the formulation in equal amounts (the
size of peas) on both sides. Patients were informed that the formulation should be applied and rubbed
gently into the skin surface (approximately 4
×
4 cm) and were supposed to apply it twice a day for up
to a period of 14 days before the follow-up visit.
2.6. Sample Size Estimation
Values of the minimum sample size were determined below in the case of Student’s t-tests for
dependent samples, assuming the target values of test power equal to 95% (0.95) and 99% (0.99) and
the significance level of the test α=0.05. The values were generated using the STATISTICA software
package, version 13.1. The results are presented in the table below (Table 3):
Table 3. Minimal sample size for Student’s t-tests for dependent samples (TP =test power).
Group Variable Correlation Minimal Sample Size
(TP =0.95)
Minimal Sample Size
(TP =0.99)
1 EMG I(P) vs. EMG II(P) 0.49282210 17 (TP =0.9563) 23 (TP =0.9915)
1 EMG I(L) vs. EMG II(L) 0.39039193 15 (TP =0.9502) 21 (TP =0.9919)
2 EMG I(P) vs. EMG II(P) 0.77346774 64047 (TP =0.9500) 90551 (TP =0.9900)
2 EMG I(L) vs. EMG II(L) 0.46762877 404 (TP =0.9502) 570 (TP =0.9900)
2.7. Statistical Analysis of Masseter Muscles Electromyographic Activity
The data obtained in experimental Group1 and in control Group 2 are available in the form of
dependent samples (the value of the statistical feature is verified before and after the placebo/CBD
formulation application), with an interval of 14 days. In statistical analysis, to demonstrate the
eectiveness of CBD formulation, the following statistical tests for dependent samples were used:
J. Clin. Med. 2019,8, 1886 9 of 17
Student’s t-test for dependent samples
Wilcoxon signed-rank test
Sign test
2.7.1. Student’s t-test for Dependent Samples
According to the Student’s t-test, since the group sizes were rather small (n=30), we performed
the Shapiro–Wilk normality test. Table 4presents the results of Shapiro–Wilk normality test.
Table 4. Normality tests of all variables.
Group Variable Test Statistic W p-Value
1 EMG I(P) 0.96100 0.32840
1 EMG I(L) 0.96796 0.48497
1 EMG II(P) 0.94409 0.11721
1 EMG II(L) 0.96608 0.43811
2 EMG I(P) 0.94729 0.14295
2 EMG I(L) 0.95238 0.19573
2 EMG II(P) 0.93287 0.05855
2 EMG II(L) 0.96379 0.38573
Table 5shows the results of Student’s t-test. The significance level of 0.05 was assumed.
Table 5. Student’s t-test for means of dependent samples.
Variable Sample Dierence in Means Test Statistic T p-Value
Group1(P) 0.036333 5.198612 0.000015
Group1(L) 0.034000 5.493967 0.000006
Group2(P) 0.000667 0.077980 0.938379
Group2(L) 0.012333 0.985221 0.332664
The null hypothesis
H0
is the normality of the distribution of the appropriate variable, with an
assumed significance level of α=0.05.
2.7.2. Wilcoxon Signed-Rank Tests
Table 6presents the results of a Wilcoxon signed-rank test (compared to the values of appropriate
variables on days 0 and 14). A significance level of 0.05 was assumed.
Table 6. Results of Wilcoxon signed-rank tests.
Variable Test Statistic W p-Value
Group1(P) 5.500000 0.000005
Group1(L) 5.500000 0.000005
Group2(P) 178.00000 0.569163
Group2(L) 194.00000 0.611352
We obtained results similar to that of Student’s t-test. For the patients treated with CBD formulation,
there was a significant improvement in masseter sEMG activity (the decrease of average rest masseter
muscle activity values).
J. Clin. Med. 2019,8, 1886 10 of 17
2.7.3. Sign Test
An alternative to the Wilcoxon signed-rank test is the Sign test. Sign test provided the following
results in Table 7(assumed for a significance level 0.05):
Table 7. Results of sign tests.
Variable p-Value
Group1(P) 0.000008
Group1(L) 0.000001
Group2(P) 0.850107
Group2(L) 0.710347
As it was shown in the sign test, a significant decrease in electromyographic activity of masseter
muscles was noted in patients treated with CBD formulation. The results of sign test match Wilcoxon
signed-rank test results. Table 8presents the normalized mean and the standard deviation of the level
of activity in rest position (RP).
Table 8. Main descriptive statistics.
Group Variable Mean Standard Deviation
1 EMG I(P) 0.273333 0.026824
1 EMG I(L) 0.270667 0.026514
1 EMG II(P) 0.237000 0.043561
1 EMG II(L) 0.236667 0.033869
2 EMG I(P) 0.292000 0.070925
2 EMG I(L) 0.299000 0.068247
2 EMG II(P) 0.291333 0.067962
2 EMG II(L) 0.286667 0.064505
2.7.4. Comparison of the Two Independent Groups (Control Formulation and CBD Formulation)
Based on the results of Student’s t-test and Mann–Whitney U-test, the eect of the treatment with
CBD formulation is clearly visible. In the case of Wald–Wolfowitz test, there is no basis to reject the
null hypothesis; however, in the case of comparison of p-values, the significance level is close to 0.05.
Table 9shows the results (p-values) of the statistical analysis.
Table 9. Comparison of Group1 “cannabidiol (CBD)” and Group2 “placebo” group.
Variable Student t-Test Wald–Wolfowitz Runs Test Mann–Whitney U-test
Group1/Group2(P) 0.005000 0.434659 0.002157
Group1/Group2(L) 0.000000 0.068318 0.001638
2.8. Statistical Analysis of Pain Intensity Changes
2.8.1. t-Student Tests for Dependent Samples
We verify the null hypothesis:
m1=m2
, where
mi
stands for the mean value of the considered
variable in the ith population,
i=
1, 2. The results of the t-student tests are given in Table 10.
The significance level 0.05 is assumed.
J. Clin. Med. 2019,8, 1886 11 of 17
Table 10. t-Student tests for means of dependent samples.
Variable Sample Dierence Means Test Statistic T p-Value
Group1 VAS 3.93 13.31971 0.000000
Group2 VAS 0.50 2.715305 0.011038
As one can observe, for the Group1 of patients treated with CBD formulation the dierence
between means on Day0 and Day14 is very large and the null hypothesis will be rejected at any level of
significance (p-value is approximately 0). In the case of Group2, patients treated with placebo, however
the hypothesis is rejected for significance level 0.05.
2.8.2. Wilcoxon Signed-Ranks Tests
To verify the null hypothesis that the use CBD formulation has no significant impact, we will use
the Wilcoxon signed-ranks test. The results of the test (we compare the values of appropriate variables
on Day0 and on Day14) presents Table 11. We assume significance level 0.05.
Table 11. Results of Wilcoxon signed-ranks tests.
Variable Test Statistic W p-Value
Group1 VAS 0.00 0.000003
Group2 VAS 37.50 0.020672
A conclusion similar to that formulated for t-Student test can be obtained. For the patients treated
with CBD formulation in Group1, the zero hypothesis will be rejected at any level of significance. In the
case of the Group2 (patients treated with placebo) the result depends on the level of significance. Such
a situation shows the essential influence of the treatment with CBD formulation for the average pain
level (the treatment gives an essential reduction of the pain level).
2.8.3. Sign Test
The sign test gives the following results (the decision is taken for significance level 0.05): Table 12
shows the results (p-values) of the statistical analysis.
Table 12. Results of sign tests.
Variable p-Value
Group1 VAS 0.000000
Group2 VAS 0.021781
As one can observe from the sign test follows a significant impact of the treatment CBD formulation
in Group1 for the decreasing of the average pain level (the conclusion the same as in the case of the
Wilcoxon signed-ranks test).
In Table 13 the results for the main descriptive statistics are presented, namely the mean and the
standard deviation for all variables in two groups.
Table 13. Main descriptive statistics for pain intensity changes in VAS Visual Analogue Scale.
Variable Mean Standard Deviation
VASI Group1 5.60 1.379655
VASII Group1 1.67 1.446359
VASI Group2 5.10 1.268994
VASII Group2 4.60 1.588754
J. Clin. Med. 2019,8, 1886 12 of 17
2.8.4. Comparison of Two Independent Groups (Group1 and Group2)
In comparing the results between Group1 and Group2 after 14 days of therapy, we use the
following tests:
Student’s t-test for independent samples means (the null hypothesis is that means are the same in
two Groups)
Wald-Wolfowitz runs test and U Mann- Whitney test (the null hypothesis is that probability
distributions are the same in Group1 and Group2)
The results (p-values) are shown in Table 14:
Table 14. Comparison of Group1 and Group2 after 14 days.
Variable t-Student Test Wald-Wolfowitz Runs Test UMann-Whitney Test
VASII Group1/VASII Group2
0.000000 0.000159 0.000000
As one can observe, if we take any significance level (not necessary 0.05), the null hypothesis will
be rejected according to all considered tests, so the impact of the treatment with CBD formulation in
Group1 is visibly essential.
3. Results
3.1. Masseter Muscles sEMG Activity Changes
According to our results, there were no statistically significant differences between the two groups in
terms of age or gender (p>0.05). In the case of Group1 after 14 day, there was a significant effect of CBD
on the average level of the rest sEMG activity of masseter muscles. In the case of Group2 after 14 days,
there was no eect of using the formulation on the average level of masseter muscle sEMG activity.
The sEMG masseter muscle activity was significantly decreased in Group1 (CBD formulation)
(11% in the right masseter muscle and 12.6% in the left masseter muscle) compared to Group2 (placebo
formulation) (0.23% in the right masseter muscle and 3.3% in the left masseter muscle). The reduction
in the mean values of sEMG after normalization of rest masseter was statistically significant in Group1
and was not significant in Group2 (Figure 4).
J. Clin. Med. 2019, 8, x FOR PEER REVIEW 12 of 17
In comparing the results between Group1 and Group2 after 14 days of therapy, we use the
following tests:
Student’s t-test for independent samples means (the null hypothesis is that means are the same
in two Groups)
Wald-Wolfowitz runs test and U Mann- Whitney test (the null hypothesis is that probability
distributions are the same in Group1 and Group2)
The results (p-values) are shown in Table 14:
Table 14. Comparison of Group1 and Group2 after 14 days.
Variable
t
-Student Test Wald-Wolfowitz Runs Test
U
Mann-Whitney Test
VASII Group1/VASII Group2 0.000000 0.000159 0.000000
As one can observe, if we take any significance level (not necessary 0.05), the null hypothesis
will be rejected according to all considered tests, so the impact of the treatment with CBD formulation
in Group1 is visibly essential.
3. Results
3.1. Masseter Muscles sEMG Activity Changes
According to our results, there were no statistically significant differences between the two
groups in terms of age or gender (p > 0.05). In the case of Group1 after 14 day, there was a significant
effect of CBD on the average level of the rest sEMG activity of masseter muscles. In the case of Group2
after 14 days, there was no effect of using the formulation on the average level of masseter muscle
sEMG activity.
The sEMG masseter muscle activity was significantly decreased in Group1 (CBD formulation)
(11% in the right masseter muscle and 12.6% in the left masseter muscle) compared to Group2
(placebo formulation) (0.23% in the right masseter muscle and 3.3% in the left masseter muscle). The
reduction in the mean values of sEMG after normalization of rest masseter was statistically significant
in Group1 and was not significant in Group2 (Figure 4).
Figure 4. Normalized surface electromyographic (sEMG) mean values of masseter muscle activity at
rest position in Group1 and Group2; on Day 0 (I) and on follow-up visit on Day 14 (II) of the therapy;
on left (L) and right (R) masseter muscle.
Figure 4.
Normalized surface electromyographic (sEMG) mean values of masseter muscle activity at
rest position in Group1 and Group2; on Day 0 (I) and on follow-up visit on Day 14 (II) of the therapy;
on left (L) and right (R) masseter muscle.
J. Clin. Med. 2019,8, 1886 13 of 17
3.2. Pain Intensity Changes in VAS Scale
In the case of Group1, there was a significant eect of CBD on the average pain level of masseter
muscles. In the case of Group2, there was no eect of using the formulation on the average pain
level of masseter muscle. It was observed in the study that pain intensity in VAS scale after 14 days
of application of CBD formulation over masseter muscles was significantly decreased in Group1
(CBD) from the average VASI =5.6 (SD =1.38) on Day 0, to VAII =1.67 (SD =1.44). Comparing to
Group2: placebo formulation application from the average VASI =5.10 (SD =1.26) on Day 0 to VASII
=4.60 (SD =1.58) on Day 14. The pain intensity in VAS scale was significantly decreased in Group1
(CBD formulation): 70.2% reduction comparing to Group2 (placebo formulation): 9.81% reduction.
The reduction was statistically significant in Group1 and was not significant in Group2 (Figure 5).
Figure 5.
Pain intensity changes in VAS scale in Group1 and Group2 on Day0 (I) and on Day 14 (II) of
the therapy.
3.3. Adverse Eects
There were no adverse eects recorded in this study.
4. Discussion
CBD is a non-psychoactive substance that can aect the treatment of many disease states, including
pain and inflammation [
10
], which is confirmed by
in vivo
studies showing CBD activity to reduce the
release of proinflammatory cytokines [
35
]. The multitude of potential uses of cannabinoids causes
a change in their perception, from recreational herbal compounds to specific drugs used in many
civilization diseases among which we can distinguish MFP.
Inhalations are the most popular way of administering the active substances contained in
cannabis [
36
]. The systemic bioavailability of CBD administered by this route is estimated at 31% [
36
].
The bioavailability of cannabidiol and delta-9-tetrahydrocannabinol in an aerosol prescribed for oral
use is estimated at 6%, and the delay of action is 120 min, much longer compared to the previously
mentioned inhalation [
36
]. Due to the limited oral bioavailability [
37
] caused by digestion, the
specificity of the location of MFP and the lipophilic nature of the test compound, it was decided to
test transdermal CBD administration [
1
,
4
]. Transdermal drug formulations have many advantages
over oral forms of drugs. Transdermal administration avoids the first-pass metabolism eect and
thus improves the bioavailability of the drug. In addition, transdermal administration allows for
constant release of the drug for a longer period of time at the application site, while minimizing the
adverse eects of higher drug concentrations, which in turn can improve the ecacy and safety of the
J. Clin. Med. 2019,8, 1886 14 of 17
patient’s pharmacotherapy. The topical application of medicinal substances is ideal for inflammation
and muscle pain.
Transdermal cannabinoids are eective in reducing pain and inflammatory symptoms [
38
,
39
].
Potential disadvantages of the percutaneous solution used, manifesting as a possible local allergic
reaction or low penetration of the drug with a hydrophilic structure can be quickly refuted. Both the
carrier in the form of cholesterol ointment and the active substance in the form of CBD are hypoallergenic
and have a lyophilic character, significantly facilitating penetration through the skin [
4
,
40
]. A very
interesting idea that may be useful in the future in myofascial pain therapy is transdermal administration
through the patches as a CBD carrier, providing even greater control over the process of release of the
active substance [37].
According to Lucas, CBD transdermal administration is 10 times higher than administration of
THC in humans [
37
]. Among all cannabinoids CBD with the most polar chemical structure should
be in favor for improved skin absorption [
37
]. That is why authors decided to evaluate CBD cream
eciency in reducing superficial electromyographic activity of masseters muscles in patients with
myofascial pain. Cannabinoids are accumulated in adipose tissues and well vascularized organs.
Cannabidiol has a long elimination half-life: 24 h after intravenous administration and 2–5 days after
repeated, daily inhalation, respectively [37].
Cannabinoids are used, inter alia, in treatment of nausea and vomiting in patients after
chemotherapy [
10
] to increase appetite in patients with AIDS, anorexia nervosa [
11
], and the pain
associated with multiple sclerosis, epilepsy (particularly in children), neurodegenerative diseases—such
as Parkinson’s disease or Huntington’s disease. In addition, THC has antimicrobial properties—it
inhibits the growth of gram-positive bacteria [4].
Wong has found that intramuscular injection of THC reversed the mechanical sensitization,
induced in masseter muscle of rats [
25
]. Authors found cannabinoids CB1 and CB2 receptors in
trigeminal ganglion, that innervated rats masseter muscles. Results of the research study on rats suggest
that cannabinoid receptors are a target for analgesic therapy in muscle pain disorders. Because of the
diculty in administering CBD to the site of action in the CB1 and CB2 receptor region, transdermal
administration seems to be optimal. In this way, the alimentary canal and intramuscular injections
are omitted. Cannabidiol, one of many cannabinoids in cannabis sativa, can be delivered through the
skin surface. The level of transdermally absorbed CBD was measured in blood plasma in rat-model
research [
36
]. After 0.62 mg CBD oil application on 3.5 cm
2
skin surface, 3.8 ng/mL (SD =1.4 ng/mL)
CBD was found in blood plasma [
36
]. CBD formulation, tested in this research was approximately
1.46% CBD, compared to 10% CBD gel used in rat-model of the transdermal cannabidiol application [
4
].
In this research study, the application was local, over the masseter muscle, so the authors are of the
opinion that local plasma levels might be lower compared with concentrated 10% gel [
1
]. Further
research is needed to determine the appropriate dose and method of CBD administration.
According to Stinchcomb expected therapeutic plasma level of CBD is 10 ng/mL in therapy of
nausea vomiting, but also in pain therapy [
41
]. The strategy “start low and go slow” seems to be the
best solution in optimal cannabinoids prescribing, choosing the best dose for a patient [
37
]. The ideal
method of transdermal use of CBD would be the aforementioned transdermal patches, with the active
substance in the form of CBD, worn on painful muscles for a long time.
No psycho-active side eects were observed in patients attending control visits, because there was
no THC in the cannabis oil, and there were no cases of hypothermia or hypomobility induced by THC.
The surface electromyography (sEMG) recordings were performed at mandibular rest position
from the masseter region and results were compared intra-session and inter-sessions after 7 and 14 days.
A frequent complaint against studies comparing EMG values is the lack of reproducibility of sEMG
measurements. However, according to a study published by Castroflorio in 2005, the analysis of the
masseter muscle activity was considered repeatable, both between visits and during one study [
42
].
Authors of the study have observed that electrode placement is critical for low-level EMG activity
J. Clin. Med. 2019,8, 1886 15 of 17
analysis, that is why they have proposed the use of the template for sEMG follow-up visits [
42
].
The template was also used during this research study.
Dysregulation of the balance between sympathetic and parasympathetic part within the
autonomous nervous system is probably a very important factor in the induction of bruxism and
myofascial pain. The autonomic nervous system regulates the body’s unconscious actions, for example
sleep bruxism. Innovative methods to reduce muscle tonus and allow masticatory muscles to recover
form myofascial pain are in demand [
43
]. CBD as a safe alternative to THC should be carefully studied
in all possible applications in medicine. Advanced clinical trials should be conducted to determine the
dose, route of administration and eectiveness of CBD in the therapy of myofascial pain of masseter
muscles. CBD is a nonpsychoactive substance with its possible use in pain therapy, in multiple sclerosis
and in the treatment of inflammation [
10
]. The oral bioavailability of CBD is limited because of the
action of digestive enzymes, but
in vivo
study has demonstrated its activity in reducing the processes
of inflammation and cytokine release [
36
]. Aerosol with CBD and delta-9-THC is prescribed for use in
the oral cavity as an anti-inflammatory therapy [
37
]. The oral bioavailability of both THC and CBD is
poor which has been evaluated to be approximately 6% and the time to action is 120 min, which is
much longer when compared to cannabis inhalation [38].
5. Conclusions
The application of CBD formulation on the masseter muscle reduces sEMG activity and pain
intensity of masseter muscles during RP and improves the condition of the muscle in patients with
MFP. Further research is needed in this field, but CBD, as an alternative for THC, should be taken into
consideration in the therapy of masticatory muscles in patients with TMD.
Author Contributions:
S.B. and A.N.-B. conceptualized the study; A.N.-B. and O.B. developed the methodology;
K.W. and W.K. performed analysis on the software; A.N.-W. performed validation; W.K. conducted formal analysis;
K.W.-D. performed investigation; P.O. and O.B. were responsible for the resources; K.W.-D. and K.W. performed
data curation; A.N.-B. wrote the original draft of this manuscript; P.O. and S.B. wrote, reviewed, and edited
the manuscript; K.W.-D. and W.K. performed visualization; S.B. performed supervision; and A.N.-B. and S.B.
undertook project administration.
Acknowledgments:
We would like to thank MedycynaCBD.pl and Maciej Pawłowski for material support:
Charlotte’s Web Hemp Extract Oil Formula Olive Oil 30 mL (A00674, product code 910.061 Stanley Brothers
Boulder CO80301) for CBD formulation preparation.
Conflicts of Interest: The authors declare no conflict of interest.
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... 79 Three studies were included in this group, with a total of 150 patients. [80][81][82] In 1 study, significant improvement in pain and better results as compared to ibuprofen were reported. 80 The remaining 2 studies reported significant improvement in pain after the topical use of CBD in patients with temporomandibular disorders (TMD). ...
... 80 The remaining 2 studies reported significant improvement in pain after the topical use of CBD in patients with temporomandibular disorders (TMD). 81,82 Table 7 shows the as compared to baseline, the VAS pain score decreased from 73.1 to 58.1, 53.2 and 51.9 at 3, 6 and 9 months, respectively (p < 0.01), pain intensity decreased from 7.5 to 6.0, 5.8 and 5.7, respectively (p < 0.01), pain frequency decreased from 7.8 to 6.4, 6.2 and 5.6, respectively (p < 0.01), insignificant pain drops included: radiating right leg pain; radiating left leg pain; leg pain intensity; ...
... Moreover, CBD application led to decreased activity and enhanced condition of the masticatory muscles. The comprehensive meta-analysis of all four studies [69][70][71][72] revealed that capsaicin, cannabis, Ping on ointment and cassumunar ginger, turmeric, and camphor exhibit greater efficacy in diminishing TMD pain compared to placebo (Fig. 4). Network meta-analysis and the ranking based on the probability of each treatment being the best were performed for the 5 interventions (Fig. 5). ...
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The pharmaceutical industry has been primarily focused on developing synthetic drugs to address orofacial pain (OFP)-related conditions. There is limited knowledge regarding the efficacy of the use of herbal extracts in treating OFP. A systematic review and a meta-analysis of 62 randomized controlled trials assessing the analgesic effects of herbal extracts on pain intensity in various orofacial conditions was conducted. The intervention comprised the use of herbal extracts compared with a placebo and/or standard treatment. The primary outcome was pain intensity assessed before and after the intervention. The pain scores were compared with the baseline scores in each treatment. When compared with standard therapy, the pooled results of the patients who received herbal extracts revealed lower pain intensity in periodontal pain (MD = -0.92[-6.69, 4.85]), oral surgery pain (MD = 18.80[8.80, 28.79]), oral neuropathic pain (MD = 20.34[6.16, 34.52]), endodontic pain (MD = -8.04[-11.72, -4.37]), oral mucosal pain (MD = 8.74[2.76, 14.73]), and temporomandibular pain (MD = 30.94[6.04, 55.83]). The findings indicated a pain-attenuating effect of herbal extracts such as cannabis, turmeric, capsaicin, licorice, ginger, chamomile, clove, Hypericum perforatum, and Arnica montana. These findings revindicate that herbal extracts may be valuable alternatives to traditional pain medications and promising source for the development of new active ingredients for pharmaceuticals. Supplementary Information The online version contains supplementary material available at 10.1038/s41598-024-77796-7.
... By potentially reducing inflammation and promoting healing, CBD might offer a more comfortable and efficient recovery for patients undergoing dental surgeries or treatments that typically result in postoperative inflammation and pain [11]. Additionally, its anxiolytic effects could be a boon for patients experiencing dental anxiety, a common barrier to seeking necessary dental care. ...
... Paralelamente, o CBD provocou uma diminuição significativa na atividade eletromiográfica (EMG) do masseter, sendo de 11% no lado direito e 12,6% no esquerdo, enquanto com placebo a atividade EMG do masseter foi de 0,23% no lado direito e 3,3% no esquerdo. Assim, apontou-se que embora haja a necessidade de mais pesquisas neste campo, o CBD deve ser considerado como uma terapia dos músculos mastigatórios em pacientes com DTM, visando-se à melhora na atividade EMG e intensidade da dor miofascial 22 . ...
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RESUMO: Introdução: Os efeitos alucinógenos e relaxantes da planta Cannabis sativa chamam atenção para as possibilidades de aplicação terapêutica há séculos. Atualmente, em território nacional, a planta é regulamentada para fins medicinais pela Agência Nacional de Vigilância Sanitária, viabilizando o composto como uma alternativa emergente na terapêutica de diversas condições clínicas, dentre elas, a Dor Orofacial. Metodologia: Realizou-se uma revisão de literatura no período de 2018 a 2023, nas bases de dados PUBMED/MEDLINE, Periódico CAPES, Scielo e Google acadêmico, utilizando os descritores "Cannabis", "Pharmacology" e “Facial Pain". Foram identificados 42 estudos científicos, nos quais, mediante a aplicação de critérios de inclusão e exclusão, 23 foram escolhidos para integrar a amostragem da presente pesquisa. Discussão: Assim sendo, como perspectivas emergentes, pode-se citar a contribuição de dados científicos relativos ao sistema endocanabinoide, aos matizes farmacológicos, à eficácia terapêutica, à aplicabilidade na Odontologia e ao emprego da Cannabis medicinal no contexto das dores orofaciais. Assim, observou-se a redução das Dores Orofaciais crônicas associadas às Desordens Temporomandibulares, além de redução da atividade muscular mastigatória, contribuindo para melhoria da qualidade de vida do paciente. A aplicação transdérmica vem demonstrando ser mais eficiente, além de minimizar reações adversas. Conclusão: Com base na literatura consultada, conclui-se que, embora ainda sejam necessários mais estudos nesse campo, a terapia canabinoide pode ser apontada como uma alternativa terapêutica para o tratamento das dores orofaciais e desordens temporomandibulares a ser considerada.
... The systematic review by Votrubec et al. [12] reveals limited evidence supporting the effectiveness of cannabinoids, with only one out of five studies noting significant benefits from a topical CBD formulation for temporomandibular disorder pain. A particularly noteworthy example is the study by Nitecka-Buchta et al. [13], which demonstrated that applying a transdermal CBD cream to the masseter muscles twice daily for 14 days significantly reduced pain intensity compared to a placebo. Chrepa et al. [14] report that CBD significantly alleviated acute dental pain, demonstrating effectiveness at various dosages and suggesting additional functional benefits, such a improved bite force, which can positively affect decreasing mechanical allodynia. ...
... This is partly attributable to the limitations of existing evidence. Among previous randomized controlled trails (RCTs) of CBD for pain, the results are inconsistent; studies mixed variable routes of administration and doses; and sample sizes were relatively small [18][19][20]. While these prior studies demonstrate the acceptability and feasibility of using CBD in conditions with symptomatic pain, ideal dosing for chronic pain is uncertain. ...
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Background Chronic pain affects over 100 million Americans, with a disproportionately high number being Veterans. Chronic pain is often difficult to treat and responds variably to medications, with many providing minimal relief or having adverse side effects that preclude use. Cannabidiol (CBD) has emerged as a potential treatment for chronic pain, yet research in this area remains limited, with few studies examining CBD’s analgesic potential. Because Veterans have a high need for improved pain care, we designed a clinical trial to investigate CBD’s effectiveness in managing chronic pain symptoms among Veterans. We aim to determine whether CBD oral solution compared to placebo study medication is associated with greater improvement in the Patient Global Impression of Change (PGIC). Methods We designed a randomized, double-blind, placebo-controlled, pragmatic clinical trial with 468 participants. Participants will be randomly assigned in a 1:1 ratio to receive either placebo or a CBD oral solution over a 4-week period. The trial is remote via a smartphone app and by shipping study materials, including study medication, to participants. We will compare the difference in PGIC between the CBD and placebo group after four weeks and impacts on secondary outcomes (e.g., pain severity, pain interference, anxiety, suicide ideation, and sleep disturbance). Discussion Once complete, this trial will be among the largest to date investigating the efficacy of CBD for chronic pain. Findings from this clinical trial will contribute to a greater knowledge of CBD’s analgesic potential and guide further research. Given the relative availability of CBD, our findings will help elucidate the potential of an accessible option for helping to manage chronic pain among Veterans. Trial registration This protocol is registered at clinicaltrials.gov under study number NCT06213233.
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Background and objectives: Sleep bruxism is a common phenomenon that can affect approximately 13% of adult population. It is estimated that bruxism can be caused by three types of factors: biological, psychological, and exogenous. There are many scientific reports about the coexistence of bruxism, stress, and psychoemotional disorders. The aim of this study is to evaluate the possible correlation between occurrence of sleep bruxism and perceived stress and depressive symptoms. Material and methods: The material of this study consisted of 77 patients of Clinic of Prosthetic Dentistry operating at the Department of Prosthetic Dentistry, Wroclaw Medical University, Poland in which after using guidelines of the American Academy of Sleep Medicine probable sleep bruxism was fund. Patients then underwent video-polysomnography. Exposure to perceived stress was evaluated with Perceived Stress Scale-10 (PSS-10). Occurrence of depressive symptoms was evaluated with Beck’s Depression Inventory (BDI). Results: The analysis showed lack of statistically significant correlation between Bruxism Episodes Index (BEI) and Perceived Stress Scale–10 and Beck’s Depression Inventory scores (p = 0.64, p = 0.65; respectively), also when comparing study group (bruxers) and control group (non-bruxers) (p = 0.88, p = 0.77; respectively). Conclusion: Intensity of sleep bruxism was not statistically significantly correlated with self-reported perceived stress and depression. This issue requires further research.
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Background and aims: To estimate prevalence of continuous use (persistence) of prescribed cannabinoid medications for up to 1 year from initial prescription in Manitoba, Canada and predictors of duration of use. Design and setting: A retrospective, population-based, cohort study using administrative data from the Manitoba Population Research Data Repository located at the Manitoba Centre for Health Policy, Canada. Participants: People without a record of a previous prescription who were prescribed a cannabinoid medication from 1 April 2004 to 1 April 2016 followed for 1 year from the date of first prescription. Measurements: Continuous prescribed cannabinoid medication use was defined as use without a gap exceeding 60 days between prescriptions. The primary outcome was prevalence of continuous prescribed cannabinoid medication use for up to 1 year. A secondary outcome was duration of continuous use. Predictors were socio-demographic characteristics, medical diagnoses and type of cannabinoid medication. Findings: Among 5452 new users, 18.1% [95% confidence interval (CI) = 17.08-19.12] were still using cannabinoids at 1 year. Median duration of use was 31 days [interquartile range (IQR) = 25-193]. This was highest for nabilone (33 days, IQR = 25-199) and lowest for nabiximols (20 days, IQR = 7-30). Use was longest among 19-45- and 46-64-year-old users and those with the highest socio-economic status. Fibromyalgia [hazard ratio (HR) = 0.89, 95% CI = 0.84-0.95], osteoarthritis (HR = 0.91, 95% CI = 0.82-0.97) and substance use disorder (HR = 0.85, 95% CI = 0.76-0.94) diagnoses were associated with longer use (HR for discontinuation-HR < 1 less discontinuation and longer use). A diagnosis of cancer was associated with shorter use (HR = 2.73, 95% CI = 2.02-3.67). Conclusions: In Manitoba, Canada approximately 18% of people prescribed cannabinoid medication continue using for at least 1 year. Duration of use varies with type of cannabinoid medication, age, socio-economic status and dagnosis.
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In the last decades, a lot of attention has been paid to the compounds present in medicinal Cannabis sativa L., such as Δ ⁹ -tetrahydrocannabinol (Δ ⁹ -THC) and cannabidiol (CBD), and their effects on inflammation and cancer-related pain. The National Cancer Institute (NCI) currently recognizes medicinal C. sativa as an effective treatment for providing relief in a number of symptoms associated with cancer, including pain, loss of appetite, nausea and vomiting, and anxiety. Several studies have described CBD as a multitarget molecule, acting as an adaptogen, and as a modulator, in different ways, depending on the type and location of disequilibrium both in the brain and in the body, mainly interacting with specific receptor proteins CB 1 and CB 2 . CBD is present in both medicinal and fibre-type C. sativa plants, but, unlike Δ ⁹ -THC, it is completely nonpsychoactive. Fibre-type C. sativa (hemp) differs from medicinal C. sativa , since it contains only few levels of Δ ⁹ -THC and high levels of CBD and related nonpsychoactive compounds. In recent years, a number of preclinical researches have been focused on the role of CBD as an anticancer molecule, suggesting CBD (and CBD-like molecules present in the hemp extract) as a possible candidate for future clinical trials. CBD has been found to possess antioxidant activity in many studies, thus suggesting a possible role in the prevention of both neurodegenerative and cardiovascular diseases. In animal models, CBD has been shown to inhibit the progression of several cancer types. Moreover, it has been found that coadministration of CBD and Δ ⁹ -THC, followed by radiation therapy, causes an increase of autophagy and apoptosis in cancer cells. In addition, CBD is able to inhibit cell proliferation and to increase apoptosis in different types of cancer models. These activities seem to involve also alternative pathways, such as the interactions with TRPV and GRP55 receptor complexes. Moreover, the finding that the acidic precursor of CBD (cannabidiolic acid, CBDA) is able to inhibit the migration of breast cancer cells and to downregulate the proto-oncogene c-fos and the cyclooxygenase-2 (COX-2) highlights the possibility that CBDA might act on a common pathway of inflammation and cancer mechanisms, which might be responsible for its anticancer activity. In the light of all these findings, in this review we explore the effects and the molecular mechanisms of CBD on inflammation and cancer processes, highlighting also the role of minor cannabinoids and noncannabinoids constituents of Δ ⁹ -THC deprived hemp.
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There is a growing body of evidence to suggest that cannabinoids are beneficial for a range of clinical conditions, including pain, inflammation, epilepsy, sleep disorders, the symptoms of multiple sclerosis, anorexia, schizophrenia and other conditions. The transformation of cannabinoids from herbal preparations into highly regulated prescription drugs is therefore progressing rapidly. The development of such drugs requires well-controlled clinical trials to be carried out in order to objectively establish therapeutic efficacy, dose ranges and safety. The low oral bioavailability of cannabinoids has led to feasible methods of administration, such as the transdermal route, intranasal administration and transmucosal adsorption, being proposed. The highly lipophilic nature of cannabinoids means that they are seen as suitable candidates for advanced nanosized drug delivery systems, which can be applied via a range of routes. Nanotechnology-based drug delivery strategies have flourished in several therapeutic fields in recent years and numerous drugs have reached the market. This review explores the most recent developments, from preclinical to advanced clinical trials, in the cannabinoid delivery field, and focuses particularly on pain and inflammation treatment. Likely future directions are also considered and reported.
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In 2013, consensus was obtained on a definition of bruxism as repetitive masticatory muscle activity characterised by clenching or grinding of the teeth and/or by bracing or thrusting of the mandible and specified as either sleep bruxism or awake bruxism. In addition, a grading system was proposed to determine the likelihood that a certain assessment of bruxism actually yields a valid outcome. This study discusses the need for an updated consensus and has the following aims: (i) to further clarify the 2013 definition and to develop separate definitions for sleep and awake bruxism; (ii) to determine whether bruxism is a disorder rather than a behaviour that can be a risk factor for certain clinical conditions; (iii) to re‐examine the 2013 grading system; and (iv) to develop a research agenda. It was concluded that: (i) sleep and awake bruxism are masticatory muscle activities that occur during sleep (characterised as rhythmic or non‐rhythmic) and wakefulness (characterised by repetitive or sustained tooth contact and/or by bracing or thrusting of the mandible), respectively; (ii) in otherwise healthy individuals, bruxism should not be considered as a disorder, but rather as a behaviour that can be a risk (and/or protective) factor for certain clinical consequences; (iii) both non‐instrumental approaches (notably self‐report) and instrumental approaches (notably electromyography) can be employed to assess bruxism; and (iv) standard cut‐off points for establishing the presence or absence of bruxism should not be used in otherwise healthy individuals; rather, bruxism‐related masticatory muscle activities should be assessed in the behaviour's continuum.
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Background Medicinal cannabis registries typically report pain as the most common reason for use. It would be clinically useful to identify patterns of cannabis treatment in migraine and headache, as compared to arthritis and chronic pain, and to analyze preferred cannabis strains, biochemical profiles, and prescription medication substitutions with cannabis. Methods Via electronic survey in medicinal cannabis patients with headache, arthritis, and chronic pain, demographics and patterns of cannabis use including methods, frequency, quantity, preferred strains, cannabinoid and terpene profiles, and prescription substitutions were recorded. Cannabis use for migraine among headache patients was assessed via the ID Migraine™ questionnaire, a validated screen used to predict the probability of migraine. Results Of 2032 patients, 21 illnesses were treated with cannabis. Pain syndromes accounted for 42.4% (n = 861) overall; chronic pain 29.4% (n = 598;), arthritis 9.3% (n = 188), and headache 3.7% (n = 75;). Across all 21 illnesses, headache was a symptom treated with cannabis in 24.9% (n = 505). These patients were given the ID Migraine™ questionnaire, with 68% (n = 343) giving 3 “Yes” responses, 20% (n = 102) giving 2 “Yes” responses (97% and 93% probability of migraine, respectively). Therefore, 88% (n = 445) of headache patients were treating probable migraine with cannabis. Hybrid strains were most preferred across all pain subtypes, with “OG Shark” the most preferred strain in the ID Migraine™ and headache groups. Many pain patients substituted prescription medications with cannabis (41.2–59.5%), most commonly opiates/opioids (40.5–72.8%). Prescription substitution in headache patients included opiates/opioids (43.4%), anti-depressant/anti-anxiety (39%), NSAIDs (21%), triptans (8.1%), anti-convulsants (7.7%), muscle relaxers (7%), ergots (0.4%). Conclusions Chronic pain was the most common reason for cannabis use, consistent with most registries. The majority of headache patients treating with cannabis were positive for migraine. Hybrid strains were preferred in ID Migraine™, headache, and most pain groups, with “OG Shark”, a high THC (Δ9-tetrahydrocannabinol)/THCA (tetrahydrocannabinolic acid), low CBD (cannabidiol)/CBDA (cannabidiolic acid), strain with predominant terpenes β-caryophyllene and β-myrcene, most preferred in the headache and ID Migraine™ groups. This could reflect the potent analgesic, anti-inflammatory, and anti-emetic properties of THC, with anti-inflammatory and analgesic properties of β-caryophyllene and β-myrcene. Opiates/opioids were most commonly substituted with cannabis. Prospective studies are needed, but results may provide early insight into optimizing crossbred cannabis strains, synergistic biochemical profiles, dosing, and patterns of use in the treatment of headache, migraine, and chronic pain syndromes.
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Zubereitungen aus der Hanfpflanze Cannabis sativa werden seit Jahrtausenden als Genussdrogen und Arzneimittel eingesetzt. Die wichtigsten Inhaltsstoffe sind das psychoaktive (−)‑trans-∆⁹-Tetrahydrocannabinol (THC), das als Partialagonist an den Cannabinoid (CB)-Rezeptoren CB1 und CB2 fungiert, und das nicht psychoaktive, pleiotrop wirkende Cannabidiol (CBD). Beide Verbindungen sind hoch lipophil wie die endogenen CB-Rezeptor-Agonisten, die Arachidonsäure-Derivate Anandamid und Arachidonoylglycerol. Die CB-Rezeptoren gehören zur Familie der G‑Protein-gekoppelten Rezeptoren und in den letzten Jahren konnten die ersten Röntgenstrukturen beider Rezeptor-Subtypen erhalten werden, die das rationale Design neuer synthetischer Liganden erleichtern werden. Neben den bereits weitgehend etablierten Indikationen wie chronischer Schmerz, Chemotherapie-induziertem Erbrechen, Spasmen bei multipler Sklerose und Kachexie gibt es Hinweise auf eine Reihe weiterer Cannabinoid-Wirkungen, die noch durch klinische Studien bestätigt werden müssen.
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Objective: This study investigated whether local intramuscular injection of non-psychoactive cannabinoids, cannabidiol (CBD), cannabinol (CBN), cannabichromene (CBC) and their combinations can decrease nerve growth factor (NGF)-induced masticatory muscle sensitization in female rats. Design: In awake rats, changes in mechanical sensitivity induced by intramuscular injection of NGF and cannabinoids were measured by applying an electronic von Frey hair over the masseter muscle to measure the withdrawal response. The effect of CBD (5 mg/ml) and CBN (1 mg/ml) or their combinations CBD/CBN (1:1 mg/ml or 5:1 mg/ml) were assessed. To confirm a peripheral action, electrophysiological experiments were undertaken in anesthetized rats to examine whether intramuscular injections of CBD (5 mg/ml) and CBN (1 mg/ml) altered the mechanical threshold of masticatory muscle mechanoreceptors. Results: In behavioral experiments, CBD (5 mg/ml) or CBN (1 mg/ml) decreased NGF-induced mechanical sensitization. Combinations of CBD/CBN induced a longer-lasting reduction of mechanical sensitization than either compound alone. No significant change in mechanical withdrawal threshold was observed in the contralateral masseter muscles and no impairment of motor function was found with the inverted screen test after any of the treatments. Consistent with behavioral results, CBD (5 mg/ml), CBN (1 mg/ml) and the combination of CBD/CBN (1:1 mg/ml) increased the mechanical threshold of masseter muscle mechanoreceptors. However, combining CBD/CBN (5:1 mg/ml) at a higher ratio reduced the duration of this effect. This may indicate an inhibitory effect of higher concentrations of CBD on CBN. Conclusions: These results suggest that peripheral application of these non-psychoactive cannabinoids may provide analgesic relief for chronic muscle pain disorders such as temporomandibular disorders and fibromyalgia without central side effects.
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There is increasing interest in the use of cannabinoids for disease and symptom management, but limited information available regarding their pharmacokinetics and pharmacodynamics to guide prescribers. Cannabis medicines contain a wide variety of chemical compounds, including the cannabinoids delta‐9‐tetrahydrocannabinol (THC), which is psychoactive, and the non‐psychoactive cannabidiol (CBD). Cannabis use is associated with both pathological and behavioural toxicity and accordingly, is contraindicated in the context of significant psychiatric, cardiovascular, renal or hepatic illness. The pharmacokinetics of cannabinoids and effects observed depend on the formulation and route of administration, which should be tailored to individual patient requirements. Both THC and CBD are hepatically metabolised, hence potential exists for pharmacokinetic drug interactions via inhibition or induction of enzymes or transporters. An important example is the CBD‐mediated inhibition of clobazam metabolism. Pharmacodynamic interactions may occur if cannabis is administered with other CNS depressant drugs and cardiac toxicity may occur via additive hypertension and tachycardia with sympathomimetic agents. More vulnerable populations such as older patients may benefit from the potential symptomatic and palliative benefits of cannabinoids, but are at increased risk of adverse effects. The limited availability of applicable pharmacokinetic and pharmacodynamic information highlights the need to initiate prescribing cannabis medicines using a "start low and go slow" approach, carefully observing the patient for desired and adverse effects. Further clinical studies in the actual patient populations for whom prescribing may be considered are needed to derive a better understanding of these drugs and enhance safe and optimal prescribing