The Acute Effects of Cannabidiol on Physiological and Subjective Responses to Endurance Exercise: A Dose-Ranging Randomised Controlled Crossover Trial

Abstract

Background: Athletes report using cannabidiol (CBD), a non-intoxicating constituent of Cannabis sativa L., to enhance post-exercise recovery and manage other health conditions (e.g., poor sleep, anxiety, concussion). However, whether CBD influences performance-related outcomes remains unclear. This study investigated the acute effects of a low, nutraceutical (50 mg) and moderate, therapeutic (300 mg) dose of CBD on physiological and subjective responses to endurance exercise in trained runners.

Results: A randomised double-blind, placebo-controlled, crossover clinical trial was conducted at the University of Sydney between 24th October 2022 and 4th March 2024. Twenty-five participants (16 male; $\dot{\text{V}}$ O_2max = 53.1 ± 7.5 mL·min kg^-1) received either 0 (placebo), 50 or 300 mg CBD 1.5 h prior to completing a 60-min, submaximal intensity (~ 70% $\dot{\text{V}}$ O_2max) treadmill run (RUN 1), followed by an incremental run to volitional exhaustion (RUN 2). Neither dose of CBD altered subjective responses (i.e., affective valence, enjoyment, perceived exertion, pain) during RUN 1, nor enjoyment, mood or anxiety following RUN 1 and 2 (p's > 0.05). CBD also had a limited effect on exercise physiology and performance, with heart rate, exercise efficiency (i.e., $\dot{\text{V}}$ O₂), $\dot{\text{V}}$ O_2peak and time to exhaustion (TTE) unchanged relative to placebo (p's > 0.05). However, 300 mg CBD decreased the respiratory exchange ratio during RUN 1 (p = 0.030) and 50 mg CBD increased blood glucose upon cessation of RUN 2 (p = 0.003), compared to placebo. There was no effect of either dose on plasma concentrations of muscle damage markers, creatine and myoglobin (p's > 0.05), but a Treatment x Time x Sex interaction was identified for the gastrointestinal barrier function marker, lipopolysaccharide, with post hoc analyses revealing higher concentrations in females Post RUN 2 on 50 mg (p = 0.032), but not 300mg CBD (p = 1.000), compared to placebo.

Conclusions: CBD (50 mg, 300 mg; acute) does not appear to alter the subjective experience of submaximal intensity exercise, impact endurance performance (i.e., TTE) or have compelling effects on physiological responses to exercise. Use of CBD by athletes is, therefore, unlikely to be ergolytic or ergogenic at low to moderate doses.

Trial registration: The trial was approved by the Sydney Local Health District's Human Research Ethics Committee (2021/ ETH11945; X21-0392) and registered prospectively with the Australia and New Zealand Clinical Trials Registry (ACTRN12622000717752).

Fig. 1

A timeline of the experimental sessions. AE: adverse events; BG: blood glucose; BL: blood lactate; BP: blood pressure; FS: Feelings Scale; GI: Gastrointestinal; hCG: human chorionic gonadotrophin pregnancy test; HR: heart rate; POMS: Profile of Mood States; RPE: Rating of Perceived Exertion; RUN 1: 60-min run at a fixed submaximal intensity (~ 70% $\dot{\text{V}}$O2max); RUN 2: Incremental run to volitional exhaustion; S-PACES: Short-form Physical Activity Enjoyment Scale; STAI-S: Short-form State Trait Anxiety Inventory; TTE: time to exhaustion; UDS: urine drug screen; USG: urine specific gravity. Note: Arrival time is approximate

Fig. 2

CONSORT diagram of the study. a. Participants were not running 40 km week⁻¹ on average for a month prior to their screening. b. Participants became unresponsive and could not be contacted

Fig. 3

Plasma concentration over time profiles for CBD and CBD metabolites during CBD300 (a) and CBD50 (b) treatment. Venous blood was collected -10-(Baseline), 75- (Pre RUN 1), 155–(Post RUN 1), 205- (Post RUN 2) and 265- (1h Post RUN 2) minutes post-drug administration. Values are mean ± SD

Fig. 4

Individual plasma CBD and CBD metabolite concentrations over time during CBD300 (dark green circles) and CBD50 (light green squares) treatment. a CBD concentrations with CBD300 treatment; b CBD concentrations with CBD50 treatment; c 6-OH-CBD concentrations with CBD300 treatment; d 6-OH-CBD concentrations with CBD50 treatment; e 7-OH-CBD concentrations with CBD300 treatment; f 7-OH-CBD concentrations with CBD50 treatment; g 7-COOH-CBD concentrations with CBD300 treatment; h 7-COOH-CBD concentrations with CBD50 treatment. Lines represent individual participant concentrations

Fig. 5

Subjective outcomes collected during RUN 1. a Affective valence; b perceived exertion; c pain; d enjoyment. EX: minutes of exercise; RPE: Ratings of Perceived Exertion; S-PACES: Short form Physical Activity Enjoyment Scale; VAS: Visual Analogue Scale. ‘ + ’ represents the mean value. a: differs from 20EX (p’s < 0.05)

Fig. 6

Cardiorespiratory measures collected during RUN 1. a. Heart Rate; b. Respiratory Rate; c. Tidal Volume; d. Minute Ventilation. bpm: beats per minute; EX: minutes of exercise; RER: Respiratory Exchange Ratio; $\dot{\text{V}}$O₂: rate of oxygen consumption; $\dot{\text{V}}$CO₂: rate of carbon dioxide production. ‘ + ’ represents the mean value a: differs from 20EX, b: differs from 40EX: c: differs from 24EX, d: differs from 37EX (p’s < 0.05)

Fig. 7

Metabolic measures collected during RUN 1. a. Relative $\dot{\text{V}}$O₂; b. Absolute $\dot{\text{V}}$O₂; c. $\dot{\text{V}}$CO₂; d. RER; e. Carbohydrate Oxidation; f. Fat Oxidation; g. Energy Expenditure CHO: carbohydrate; EX: minutes of exercise; RER: Respiratory Exchange Ratio; $\dot{\text{V}}$O₂: rate of oxygen consumption; $\dot{\text{V}}$CO₂: rate of carbon dioxide production. ‘ + ’ represents the mean value. c: differs from 24EX, d: differs from 37EX (p’s < 0.05)

Fig. 8

Capillary blood lactate (a) and glucose (b) concentrations collected upon cessation of RUN 1. Individual shapes represent individual participant values; bars represent mean values. *: differs from Placebo (p < 0.05)

Fig. 9

Performance measures collected during RUN 2. a. Time to Exhaustion; b. Peak Heart Rate; c. $\dot{\text{V}}$O_2peak; d. RER_peak; e. Lactate concentrations; f. Glucose concentrations. RER: Respiratory Exchange Ratio; $\dot{\text{V}}$O₂: rate of oxygen consumption; $\dot{\text{V}}$CO₂: rate of carbon dioxide production. Individual shapes represent individual participant values; bars represent mean values. *: differs from Placebo (p < 0.05)

Fig. 10

Plasma lipopolysaccharide concentrations in a. Male participants (n = 16) and b. Female participants (n = 9). BSL: Baseline; POST: 1h Post RUN 2. Values are Mean ± SD.*: CBD50 differs from Placebo (p < 0.05); a: differs from Baseline (p’s < 0.05)

Fig. 11

Exercise enjoyment as measured by the 18-item Physical Activity Enjoyment Scale (PACES) before exercise (PRE) and after RUN 1 and RUN 2. ‘ + ’ represents the mean value

Fig. 12

Muscle and gastrointestinal damage biomarkers. a. Creatine Kinase; b. Myoglobin; c. Lipopolysaccharide. BSL: Baseline; POST: 1h Post RUN 2. Values are Mean ± SD. a: differs from Baseline, b: differs from Post RUN 1, c: differs from Post RUN 2 (p’s < 0.05)