The Effects of Cannabidiol Oil on Noninvasive Measures of Muscle Damage in Men

Kristen C. Cochrane-Snyman; Candelaria Cruz; Jacobo Morales; Michael Coles

Disclosures

Med Sci Sports Exerc. 2021;53(7):1460-1472. 

In This Article

Discussion

The results of the present study did not support the hypothesis that CBD oil supplementation would have an effect on noninvasive markers of muscle damage and inflammation after an ECC protocol. Within the present study, the changes observed across time were consistent with patterns expected as a result of ECC-induced muscle damage. Previous studies[9,13,16,47–49] have indicated that performing repetitive ECC exercise results in muscle damage in the working muscle, leading to muscle soreness and inflammation. EIMD results from mechanical injury and biochemical mechanisms. Damage to structural components of sarcomeres, such as the z-line and contractile filaments, may cause the release of proteolytic enzymes and proinflammatory cytokines associated with an acute inflammatory response.[50] Thus, performing high-volume ECC exercise provides the modality to investigate EIMD and associated noninvasive markers of that damage.

The exercise protocol used in this study was similar to that of previous studies[9,16,51] used to induce muscle damage in the forearm flexors. In the present study, there was a 12% reduction in PT when collapsed across conditions from pretest to posttest. Although statistical significance was not met at the 0.05 level across all visits, absolute PT remained depressed at 24, 48, and 72 h post across both conditions (Figure 5). Reductions in PT were, however, less than those reported in previous studies.[9,16] For example, Beck et al.[16] reported between 21% and 43% reductions in PT, whereas Jenkins et al.[9] reported PT reductions between 23% and 44% after ECC exercise. The present study utilized untrained participants, which was similar to Jenkins et al..[9] It has been reported[50] that untrained participants may require verbal encouragement during maximal voluntary tasks, such as a MVIC, to ensure that accurate measures of maximal voluntary PT are achieved before the test. For example, the authors[50] found a 5% increase in peak force when untrained individuals were given verbal encouragement during isometric contractions of the elbow flexors. Verbal encouragement was provided that was consistent with current recommendations and in agreement with the methods of Beck et al.[16] and Jenkins et al..[9] In addition, pre-MVIC measures were found to be consistent across conditions. Despite differences in the magnitude of change reported for PT, time-dependent changes in PT after high-volume ECC exercise has been shown to be a potent indicator of muscle damage.[52] Thus, the change in PT, although limited, indicates that muscle damage was induced as a result of the ECC exercise protocol.

Acute muscle soreness occurs during or immediately after performing high-volume eccentric or novel exercise. It has been demonstrated[11,50] that acute soreness may progress into DOMS within 24 h before subsiding ~5 or fewer days after exercise. Pain, stiffness, tenderness, and swelling are all common symptoms of exercise-induced muscle soreness.[12] Stiffness after exercise is believed to occur as a result of connective tissue damage, which often accompanies EIMD. Damage to connective tissues increases mechanical sensitivity within nociceptors and stretch receptors in the muscle resulting in discomfort and pain upon activation.[50] The present study demonstrated increases in perceived soreness from pre-ECC to post-ECC and at 24, 48, and 72 h after completion of the ECC protocol. In addition, peak soreness occurred within 24–48 h after performing the exercise protocol, which coincided with a decrease in JA from pretest to posttest and 48 h posttest (Figures 2, 4) and was consistent with the time course of DOMs. In a similar study investigating the effectiveness of a tobacco-derived supplement on muscle damage, Jenkins et al.[9] reported increases in soreness and decreases in JA after the same ECC procedures but no effect of supplementation on these time-dependent changes. These findings were similar to the present study in that changes in perceived soreness and JA did not differ between CBD and PLC conditions. Previous research[53] has demonstrated that CBD interacts with adenosine A2A receptors, which can protect tissue from inflammatory damage. This effect, at doses as low as 1 mg·kg−1, was most markedly shown via downregulation of TNF-α.[53] It has also been reported[54] that CBD's interaction with the CB2 cannabinoid receptor can disrupt the arachidonic acid inflammatory pathway involved in the development of inflammation and edema. The bulk of this direct, inflammatory evidence comes from rodent models.[53,54] Thus, there may be a dose-dependent difference in the effectiveness of CBD on A2A and CB2 receptors in response to the persistent inflammation associated with EIMD. In the present study, the lack of condition-specific differences in responses for perceived soreness and JA supported the manifestation of acute muscle damage, but not the efficacy of the current dose and schedule of CBD oil as a means of reducing these noninvasive measures of muscle damage.

Arm circumference did not change as a function of drug condition, which indicates that any active ingredient in CBD did not affect swelling more than the control. There was, however, a transient increase in arm circumference from pretest to posttest (Figure 3) that tracked the modest decline in PT (Figure 5). It is common to observe increases in limb circumference following acute exercise because of cell and fluid migration from circulation into the interstitial spaces that surround muscle fibers.[5] Any fluid shift that may have resulted from ECC exercise and subsequent arm swelling (arm circumference) detected immediately after ECC protocol was not deemed to be statistically significant at 24, 48, or 72 h post. It has been shown in rodent models[29] that CBD oil can exert an anti-inflammatory effect reducing edema in response to oral dosages of 5–40 mg·kg−1 for a sequence of 72 h after induced inflammation via carrageenan injection. These effects were attributed to the interaction of CBD with A2A receptors and a reduction of cyclooxygenase activity. In the present study, the average dose received per kilogram body mass was approximately 2.0 mg·kg−1, which was less than the average doses shown to be effective in rodent models but similar to doses shown to be effective at reducing neuroinflammation in human subjects.[41] These findings indicate that there may be more variation in effective dose requirements across different forms of inflammation in human models (neuro vs EIMD) and those models of inflammation tested in rodent models. In addition, the results of the present study indicate that the transient increase in arm circumference reflected a transient fluid shift as a result of local swelling and increases in intramuscular pressure[55] common to acute ECC exercise, but sit was likely not dependent on the PLC effect or CBD oil supplementation in the current dose and administration schedule.

In recent years, the application of CBD for the treatment of various medical conditions has been on the rise. Previous studies[4,27] have reported improvements in symptoms of arthritis, multiple sclerosis, and neuroinflammation with the use of CBD oil. For example, administering 5 mg·kg−1 of CBD per day via i.p. or 25 mg·kg−1 given orally was shown to have an optimal effect in the suppression of gene-related and inflammatory markers associated with arthritis in mice, specifically glial fibrillary acidic protein, inducible nitric oxide synthase (iNOS), and IL-1β.[4] CBD has also been shown to reduce Aβ-induced neuroinflammation after administering 2.5 or 10 mg·kg−1 via i.p. by impairing iNOS and IL-1β protein expression. β-amyloid is found within complex extracellular lesions of senile plaques, a hallmark of Alzheimer's disease. Activation of Aβ-induced glial cells triggers an inflammatory response, in which there is a release of neurotoxic cytokines (e.g., IL-1β). Interleukin-Ib plays a significant role in the cytokine cycle of both cellular and molecular events that are accountable for neurodegenerative consequences, such as the synthesis and processing of amyloid precursor proteins, and the activation of astrocytes with a consequent overexpression of iNOS and an overproduction of nitric oxide. Nitric oxide is a free radical that is short-lived and diffusible and supports the detrimental progression of Alzheimer's disease.[56] In addition, Costa et al.[56] reported that pain within an acute carrageenan-induced inflamed rat paw was significantly reduced with oral doses of CBD as low as 5 and 7.5 mg·kg−1. The authors[56] also reported that edema within the injected rat paw decreased with dosages of 5, 7.5, 10, 20, and 40 mg·kg−1 of CBD. Although this study did not investigate a neurogenerative disease condition, these known markers targeted by CBD may provide insight into their mechanism of action during other inflammatory conditions, such as EIMD, which is characterized by swelling, inflammation, and mild edema in humans.

In the present study, CBD oil was administered after a bout of EIMD in an attempt to ameliorate soreness, inflammation, and performance declines typical after bouts of repeated, muscle damaging, ECC exercise. After performing 6 sets of 10 repetitions of ECC muscle actions of the forearm flexors, acute decreases in performance, JA, and increases in swelling and RPE were observed. However, the results of this study indicated that a dose of 150 mg (or approximately 2 mg·kg−1 of non-THC containing CBD oil administered three times from POST to 48 h post (total dose of approximately 6 mg·kg−1 had no significant effect on noninvasive measures of muscle damage and inflammation. For example, the present study found no significant condition–time interactions or main effects for condition for perceived soreness, arm circumference, JA, PT, and RPE (P > 0.05) The lack of significant interactions or main effects for condition in the present study indicated that there was no placebo or drug effect related to the ingestion or perceived ingestion of CBD. These findings differed from previous studies[9,16,17] related to inflammatory conditions but were unique findings related to the application of CBD to EIMD.

Many of the previous studies that have examined CBD's effects have been conducted using animal models that examined specific medical conditions that may utilize alternative inflammatory pathways compared with EIMD.[3–5,29] For example, CBD is capable of reducing neuroinflammation associated with Alzheimer's disease through glial pathways demonstrated by significantly reducing IL-1β and iNOS upregulation.[4] Furthermore, inflammation associated with arthritis is largely mediated by the release of TNF-α. Malfait et al.[5] reported that, in vivo, when CBD injected i.p. with 10 mg·kg−1, it suppressed lipopolysaccharide-induced serum TNF-α. The authors[5] suggested that CBD's immunosuppressive effects could be the result of a combination of both a T-helper 1 response and an anti-inflammatory action by way of decreasing TNF-α in the synovium. It has been demonstrated[51] that inflammation related to EIMD may be facilitated by the release of intercellular enzymes and muscle proteins such as CK, myoglobin (Mb), and lactate dehydrogenase (LDH), as well as the release of proinflammatory cytokines such as IL-1, IL-6, and TNF-α. Although CBD was able to suppress TNF-α via the A2A and CB2 receptor-mediated pathways in arthritis, other inflammatory mediators are still present, and more research is needed to understand the pathways in which CBD elicits its effects after EIMD in humans. Nonetheless, it is important to note that previous studies[4,5,29,41,53] had reported dose-dependent effects, meaning it is possible that the dosage and/or dose scheduling in the current study may not have been sufficient to produce reported therapeutic effects.

In the present study, a 150-mg dose of CBD was given to subjects via oral ingestion in two separate 75-mg doses to be separated by 8 h over the course of 4 d, for a total approximate dose of 6 mg·kg−1. The dose that was administered in the present study was selected, as it is considered within the typical range of commercial supplement doses and is more commonly used on a recreational basis.[57] Although 150 mg of CBD is within the typical dose range reported and has been used in previous human studies[58,59] investigating other clinical conditions, a limitation of funding prevented the use of multiple dosages and schedules within the present study. Dosages, within the present study, were also separated by 8 h. Only one previous study[17] has reported on the effect of CBD mixed with MCT oil on markers of muscle damage in trained men. This study[17] induced damage in the leg extensors and found that a significantly lower mixed dose of CBD (16 mg total mixed dose) improved perceived soreness after EIMD. However, this study did not test CBD only; thus, it is unclear how results may have differed without the confounding interaction of MCT oil. Other studies[25,60] have used similar dose schedules to investigate the effects of ibuprofen on DOMS and muscle performance after performing exercise. Nevertheless, the present study revealed that in humans a relative dose of approximately 2 mg·kg−1·d−1 and dose schedule is likely ineffective in reducing muscle soreness, inflammation, and muscular performance in untrained college-age men. Because CBD has been shown to be dose-dependent and prescribing guidelines are lacking, more research should be done using a greater range of dosages and dose schedule for its application to EIMD.

Many studies[9,16,37] have used noninvasive markers of muscle damage to determine muscle inflammation. It is common to observe an increase in inflammatory cells after performing exercise.[14,51] For example, MacIntyre et al.[14] reported an increase in the accumulation of neutrophils and cytokines, such as IL-6, after ECC exercise of the quadriceps. It is also common to observe an increase in intramuscular proteins and serum enzymes, such as CK, LDH, and Mb after ECC exercise. This is because the damage caused by ECC exercise causes tearing and leakage of intramuscular proteins and serum enzymes from myofibrils, which exacerbates the inflammatory response.[15] Jenkins et al.[51] reported that increases in CK, LDH, and Mb observed from their study occurred as a result of muscle damage caused by the ECC exercise protocol. Studies investigating the effects of CBD typically measure the accumulation of leukocytes, and/or proinflammatory cytokines such as IL-1, IL-6, and TNF-α. However, very few have investigated CBD's effects on intramuscular proteins and enzymes, such as CK, LDH, and Mb, which occur as a result of muscle damage after exercise. Therefore, prospective studies should investigate the effects of CBD on intramuscular proteins and enzymes using more invasive measures.

In the present study, CBD supplementation at 150 mg·d−1 was found to have no effect on the noninvasive assessment of muscle soreness, inflammation, and strength performance after bouts of ECC exercise of the elbow flexors in men. Because of the unique nature of CBD oil, it is possible that the pathways in which CBD may elicit its anti-inflammatory and antihyperalgesic effects may not have any influence on the recovery of muscle function after EIMD. The lack of difference between conditions and lack of interaction between condition and time indicated that at the current dose and schedule, CBD oil may not be beneficial for untrained, college-age men as a recovery aid after EIMD. Although this study did not find a significant benefit of CBD oil, it will inform future studies investigating the efficacy of CBD oil for the relief of soreness and inflammation after exercise. It is recommended that future studies investigate wider ranges of CBD dosages and scheduling in both trained and untrained men and women. The application of invasive measurement techniques such as the collection of blood serum indices to further examine CBD's therapeutic potential as a muscle recovery aid after EIMD may also elucidate the mechanistic pathways mediated by CBD oil as well as help to differentiate perceived versus physiological effects of the supplement.

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