Nowadays, dental practitioners are more obliged to treat patients suffering 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 of temporomadibular disorders (TMD). Bruxism is a common phenomenon that can affect from 8 to even 31% of the population without significant differences 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 effort 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 effect 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 different 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 affects the pharmacological effect of the cannabis extract [7]. Psychoactive effect 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]:

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 different species of cannabis, its use depends on the application and 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 effect, but it affects the psychoactive induction pathway caused by the action of THC [14]. CBD possesses anti-inflammatory and anti-nociceptive properties [15,16,17,18].

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 12–15 weeks up to 1 year of therapy [20].

In the human body, cannabinoids show their effect via two types of cannabinoid receptors: CB₁—found primarily in the central nervous system and CB₂—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). CB₁ 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].

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].

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.

This is a parallel-group, double-arm, randomized, double-blind clinical trial conducted to assess the myorelaxantand antinociceptive effect 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.

CBD is a non-psychoactive substance that can affect 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 effect 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 effects of higher drug concentrations, which in turn can improve the efficacy and safety of the patient’s pharmacotherapy. The topical application of medicinal substances is ideal for inflammation and muscle pain.

Transdermal cannabinoids are effective 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 efficiency 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 difficulty 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 cm² 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 effects 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 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 effectiveness 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].

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.

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.

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.

The authors declare no conflict of interest.