New research reveals that CBD not only enhances endurance in mice but does so by transforming gut bacteria and optimizing muscle function, offering a potential breakthrough in performance science.

Study: Cannabidiol reshapes the gut microbiome to promote endurance exercise in mice. Image Credit: Oleksandrum / Shutterstock.com

A recent Experimental & Molecular Medicine study determines whether improvements in exercise performance through cannabidiol (CBD) treatment are due to changes in the gut microbiome.

What is CBD?

The Cannabis sativa plant synthesizes over one hundred phytocannabinoids, including CBD and tetrahydrocannabinol (THC), which induce psychoactive and non-psychoactive effects, respectively. Numerous studies have reported the wide range of pharmacological properties associated with CBD, some of which include antiepileptic, antidiabetic, antipsychotic, neuroprotective, and anti-inflammatory effects.

To date, Epidiolex is the only CBD drug that has been approved by the United States Food and Drug Administration (FDA) for the treatment of seizures in patients with genetic epilepsy.

The role of CBD in improving exercise capacity

CBD influences skeletal muscle function by affecting the transcription of several genes in myotubes and conferring protection against oxidative stress. It has also been shown to improve skeletal muscle regeneration and strength after resistance training by enhancing the muscular lipid profile in mice and rats consuming a high-fat diet. Nevertheless, the impact of CBD on human skeletal muscle performance remains unclear.

An individual’s capacity to exercise depends on the fitness and adaptability of their skeletal muscle. Skeletal muscle contains type I and type II fibers with distinct myosin heavy chain (MyHC) isoforms that determine muscle contraction rates. For example, slow-twitch fibers are abundantly present in the soleus (type I), whereas fast-twitch fibers are primarily found in the extensor digitorum longus (type II).

Muscle fiber composition dynamically changes through different physiological stimuli, including endurance exercise. Endurance training generally induces mitochondrial biogenesis signaling pathways to meet increased metabolic demands.

Adenosine monophosphate (AMP)-activated protein kinase (AMPK), peroxisome proliferator-activated receptor γ (PPARγ) coactivator-1α (PGC-1α), and cyclic AMP (cAMP) response element-binding protein (CREB) are crucial molecules involved in coordinating complex cellular processes within muscles. This has led researchers to investigate the potential utility of targeting these molecules to enhance exercise performance through mitochondrial biogenesis.

About the study

The unique interplay between exercise performance and the composition of the gut microbiota led the current study’s researchers to examine whether CBD improves exercise performance by modulating gut microbial composition in mice.

Herein, 20-week-old male mice were housed under a 12-hour light-dark schedule with food and water available ad libitum. After one week of acclimatization, body fat and lean body mass measurements of the test mice were obtained. The first cohort of mice were orally treated with 30 mg/kg CBD dissolved in corn oil once daily for four weeks or dimethyl sulfoxide (DMSO), which served as the vehicle control.

A second group of mice was used to investigate whether antibiotic treatment influences the CBD effect. To this end, mice were treated with 40 mg/kg doxycycline alone or in combination with CBD, following which treadmill performance was assessed.

Faecalibaculum rodentium or Bifidobacterium animalis was orally introduced once daily for four weeks in the third cohort of mice at a dose of 1 × 10⁸ colony-forming units (CFU).

Study findings

CBD treatment increased running distance and extended the time to exhaustion in mice without significantly impacting body weight. Mice treated with CBD also exhibited stronger tetanic contractions and greater resistance to fatigue.

The hind limb muscles of mice treated with CBD appeared more red, thus indicating oxidation of muscle fibers. Increased immunofluorescent staining of type I and II MyHC isoforms oxidative fibers, otherwise known as MyHC-I and MyHC-IIa, respectively, as well as reduced staining of type II glycolytic fibers (MyHC-IIb), was observed in the gastrocnemius (GAS) muscle following CBD treatment.

GAS muscle tissue of mice treated with the CBD group also exhibited increased messenger ribonucleic acid (mRNA) expression of Myh7 and Myh2, as well as lower expression of Myh4 and Myh1. Indirect calorimetry analysis indicated a shift from glucose to fatty acid oxidation.

As compared to DMSO-treated mice, a greater prevalence of fused intermyofibrillar mitochondria was observed in the CBD group. A significant increase in mitochondrial DNA (mtDNA) content was also associated with CBD treatment, which suggests that CBD improves muscle oxidative phosphorylation (OxPhos) capacity through mitochondrial biogenesis and dynamic alterations.

CBD treatment also activated AMPK and PKA, in addition to increasing downstream CREB phosphorylation and PGC-1α levels.

The abundance of Bacillota and Actinomycetota also increased following CBD treatment. More specifically, CBD administration significantly increased the proportion of Allobaculum and Faecalibaculum of the Erysipeltrichaceae family, as well as Bifidobacterium of the Bifidobacteriaceae family. Erysipelotrichaceae and Bifidobacteriaceae species also positively correlated with enhanced muscular endurance following CBD treatment.

CBD treatment significantly increased the proliferation of B. animalis (KBP-1), which belongs to the Bifidobacteriaceae family. Notably, KBP-1 improves exercise endurance by modifying muscle fiber type and metabolic substrate utilization. It also increases the expression of genes associated with branched-chain amino acid (BCAA) biosynthesis and release pumps, as well as lactic acid metabolism.

Conclusions

CBD treatment appears to improve exercise performance and mitochondrial function in the skeletal muscle by inducing several changes in the gut microbiota, including increased production of KBP-1, which promotes exercise endurance.