Orally Ingested Transient Receptor Potential (TRP) Channel Activators Attenuate the Intensity‐Duration of Voluntarily Induced Muscle Cramps in Humans
Authors: Craighead Daniel H , Shank Sean W , Alexander Lacy M , Kenney W. Larry 
Published: November 2023

Transient receptor potential (TRP) ion channels in the mouth, esophagus and stomach are activated by ingestion of many naturally occurring food extracts. Recent evidence suggests that oral ingestion of TRPA1 and TRPV1 channel agonists may reflexly attenuate the intensity and/or duration of electrically induced muscle cramps in humans (Short et al., 2014, 2015; Hegarty et al., 2015), presumably by dampening alpha motor neuron excitability. To test this effect on voluntarily initiated calf muscle cramps, we conducted a randomized, double‐blinded, vehicle‐controlled crossover study. Subjects performed 3 baseline experiments in which they underwent a voluntary exercise‐induced muscle cramp protocol. From an original pool of 34 volunteers with a self‐reported history of exercise‐related muscle cramping, 6 men and 14 women (age: 22±3 yrs representing 59% of screened subjects) were able to consistently reproduce cramps voluntarily. Each of the 20 enrolled subjects subsequently participated in 2 experimental trials, one 15 min after consuming less than 3 oz. of an active (A) formulation containing a mixture of TRPA1 and TRPV1 activators derived from natural extracts and another 15 min after ingesting a vehicle control (V) in a randomized sequence. EMG leads were placed on the medial gastrocnemius, lateral gastrocnemius, soleus, and tibia. The supine subject's foot was securely strapped to an adjustable force transducer and the knee flexed to position the foot at the angle of maximum plantar flexion. As directed by the experimenter, the subject then attempted to produce a cramp by first pre‐shortening the gastrocnemius, isolating the triceps surae, and then performing a maximal voluntary static contraction (MVC). Contractions were held for 90 s or until a cramp occurred. If no cramp occurred, subjects rested for 10 min before attempting to elicit a cramp for a second time. Subjects repeated this pattern for up to 5 attempts within any given experiment; all experiments were separated by at least 1 week. EMG and force were recorded at baseline, during the static muscle contraction, and throughout the duration of the muscle cramp. There were no significant differences between active and vehicle control for pre‐cramp MVC (A: 12.4±7.0 (SD) kg, V: 12.5±7.6 kg; p=0.99), post‐cramp MVC (A: 10.1±5.6 kg, V: 10.7±6.8 kg; p=0.40), pre‐cramp contraction duration (A: 32.7±21.8 s, V: 28.3±17.2 s; p=0.16), or cramp duration (A: 13.7±11.4 s, V: 16.9±16.3 s; p=0.08). However, the integrated EMG signal, i.e., the area under the EMG intensity‐duration curve, was significantly lower (p=0.01) for A (0.51±0.38 V•s) than V (0.80±0.69 V•s). Composite subjective ratings of soreness (on a 1 to 10 rating scale) during the initial 20 min after cessation of cramping were also significantly (p=0.02) lower for the active formulation (3.4±4.6) than the vehicle control (4.0±2.2). Consistent with results from studies that have evoked leg muscle cramps using electrical stimulation, oral TRP channel activators significantly attenuated the intensity‐duration profile of voluntarily initiated muscle cramps in this sample of young adults.

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FUNDING: Flex Pharma, Inc.