Myofascial pain is a significant factor in TMDs, affecting a large part of the adult population and causing marked losses in quality of life.¹³ The most frequent management methods include Non-Steroidal Anti-inflammatory Drugs (NSAIDs), tricyclic antidepressants, neuroleptics, muscle relaxants, and physical interventions. These methods produce risks of long-term adverse effects from drugs and the discomfort associated with invasive techniques, reinforcing the need for additional therapies that work in an integrated manner on the peripheral, central, and psychosocial components of myofascial pain.^14,15 In this context, this study evaluated the effects of combined sublingual Δ9-THC and CBD (10 mg/day, 1:1 ratio) therapy on myofascial pain modulation compared to placebo, over 180-days of follow-up.

The findings demonstrated a robust analgesic effect on all evaluated outcomes after using Δ9-THC/CBD. Regarding pain intensity, the reductions in the VAS were higher than those in pilot trials with CBD used alone for musculoskeletal diseases¹⁶ and dry needling protocols,¹⁷ which did not present concomitant functional gains. Reviews of cannabinoids in chronic musculoskeletal pain also reported lower decreases in pain than those of the present study, although they highlighted the good tolerability profile of these substances.⁵ These findings suggest a superior analgesic capacity of the combined Δ9-THC/CBD regimen and indicate functional synergy between the two phytocannabinoids in modulating nociception, in line with preclinical studies demonstrating lower nociceptive excitability and muscle inflammation by this combination.¹⁸

Although few clinical studies have directly quantified improvements in mandibular protrusion and lateral excursions using conventional or cannabinoid treatments, the findings of the present study highlight the relevance of cannabinoid therapy and verified functional gains. In this scenario, Vieira et al.¹⁹ evaluated the combined effect of manual therapy and physical exercise. Although the authors considered an outcome aimed at mouth opening, their findings were comparable to the gains observed in the present study for protrusion and lateral excursions (greater than 4 mm), suggesting that the combined Δ9-THC/CBD regimen may offer functional efficacy equivalent to that of conventional rehabilitation protocols. Similarly, a recent study on multiple sclerosis found that cannabinoids may significantly reduce muscle spasticity and help rehabilitate patients with debilitating symptoms of disability.²⁰ Additionally, a systematic review by Walczyńska-Dragon et al.²¹ on the therapeutic potential of CBD in TMD and orofacial pain suggested that CBD may relieve TMD-related pain and muscle tension with minimal adverse effects. Although specific effects on protrusion and laterality have not been directly evaluated, reducing muscle pain and tension may help improve mandibular function.

The placebo effect in TMD treatment revealed partial improvement in right laterality, suggesting that non-treatment-specific factors are also relevant in perceiving symptom relief. Physiologically, the placebo effect can be explained by several neurophysiological mechanisms, such as opioid, endocannabinoid, oxytocin, vasopressin, and dopamine systems, which release endorphins and modulate pain pathways in the central nervous system. These mechanisms may be activated simply by patients believing they are receiving an effective treatment.22, 23, 24 Psychologically, patients' expectations regarding treatment effectiveness may trigger a pain relief response, which is amplified by the positive emotional aspect associated with confidence in the therapeutic process.22, 23, 25 These effects highlight the importance of strict blinding in clinical trials, as they ensure that patients are not influenced by their expectations of treatment. The placebo effect may be induced by verbal cues, classical and non-classical conditioning, and social interactions, which help form expectations based on previous experiences and the observation of others.^22,23 Moreover, communication with participants regarding the nature of the study should be carefully managed to prevent an expectation bias, ensuring the validity of results and minimizing the impact of the placebo effect on the evaluated outcomes.²⁶

The analysis of qualitative outcomes of allodynia, hyperalgesia, and functional pain presented a substantial decrease in the prevalence of these symptoms among participants undergoing cannabinoid therapy. The relevant reduction in the number of patients who reported functional pain after treatment with sublingual Δ9-THC and CBD may suggest that the therapy impacts pain relief associated with myofascial pain and other chronic musculoskeletal disorders. This effect is particularly significant considering the current scenario of conventional TMD treatments, which often have limitations, especially concerning adverse effects.³

Cannabinoids, particularly Δ9-tetrahydrocannabinol (Δ9-THC) and Cannabidiol (CBD), have shown significant potential in modulating myofascial pain by acting on multiple mechanisms in the peripheral and central nervous systems.²⁷ Δ9-THC, an agonist of cannabinoid receptors CB1 and CB2, provides an analgesic effect by modulating pain transmission, reducing nociceptive activity in the central nervous system, and decreasing peripheral inflammation.^28,29 CBD, in turn, acts as an indirect modulator of these receptors, promoting anti-inflammatory and analgesic effects with a more pronounced influence on CB2 receptors in peripheral tissues, such as skeletal muscles, suggesting a direct therapeutic effect on myofascial pain.²¹ Together, these compounds demonstrate a synergistic effect, reducing inflammation and pain with a complementary action in controlling systemic and local inflammatory responses.³⁰ The activation of CB1 receptors in the central nervous system may interfere with pain perception, and the stimulation of peripheral CB2 receptors has effectively modulated inflammatory signals, which is crucial in chronic musculoskeletal pain.³¹ These mechanisms are particularly relevant in TMD, where myofascial pain is a common condition associated with changes in masticatory muscles and local inflammation. Therefore, cannabinoids have a high therapeutic potential in managing these conditions by offering an alternative for patients with chronic musculoskeletal pain who do not respond adequately to conventional treatments. These substances may also improve factors such as stress and anxiety, often present in the maintenance of chronic pain.³²

This study has limitations inherent to its non-randomized design and the absence of a washout period between phases, which could potentially lead to biases related to sequence and carryover effects. However, the likelihood of these effects occurring is minimal, as only the patient was blinded, and the study began with the use of a placebo. This design allowed the evaluator to be confident that there was no carryover, without compromising the internal validity of the findings. The methodological decision to use a fixed order was based on ethical and operational restrictions. The temporal extension of the phases and the continuous longitudinal monitoring of participants sought to minimize residual interference, although without a specific statistical analysis for the carryover effect. The duration of each phase (90-days for the placebo and 90-days for the pharmacological intervention) was also planned to reduce overlapping effects. Additionally, the absence of a valid inferential statistical analysis for allodynia, hyperalgesia, and functional pain indicates that, although the findings are promising, caution is needed when interpreting them. The small number of reported events hindered more detailed comparisons and the generalization of results to broader populations. This limitation is frequent in pilot studies and underscores the need for larger sample sizes and greater statistical power in future research.¹⁰ Another limitation of this study is the absence of stress and anxiety assessments. While participants’ experiences were qualitatively explored, quantifying the emotional impact of the intervention and examining its associations with clinical outcomes would provide a more comprehensive understanding of the potential effects of phytocannabinoids. Future studies should be adequately powered and incorporate these outcomes to strengthen the evaluation of emotional state changes associated with this therapy.

Conversely, the employed crossover design enabled the control of interindividual variability, increasing the estimated accuracy of intervention effects using a relatively small sample. Validated and standardized clinical instruments for measuring pain intensity, myofascial sensitivity, and mandibular functional parameters, associated with rigorous prospective follow-up, provide methodological robustness and reliability to the outcomes.

Although the preliminary findings, such as those in this study, suggest an improvement in functional pain, further studies on the effects of cannabinoids on TMD and other musculoskeletal conditions are necessary for a better understanding of the efficacy, action mechanisms, and adverse effects of this therapy. Regarding future investigations, crossover randomized clinical trials with sequence randomization and inclusion of appropriate washout periods are recommended to mitigate biases and improve internal validity. Expanding the sample size and incorporating clinical biomarkers may broaden the generalization and understanding of the action mechanisms of cannabinoids in the context of TMD.