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Cannabidiol and Sports Performance: a Narrative Review of Relevant Evidence and Recommendations for Future Research Open Access This article is licensed under a Creative Commons Attribution 4.0 Potential Role of Cannabidiol on Sports Recovery: A Narrative Review This is an open-access article distributed under the terms of the Creative Commons Attribution License (CC BY). The use,

Cannabidiol and Sports Performance: a Narrative Review of Relevant Evidence and Recommendations for Future Research

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Abstract

Cannabidiol (CBD) is a non-intoxicating cannabinoid derived from Cannabis sativa. CBD initially drew scientific interest due to its anticonvulsant properties but increasing evidence of other therapeutic effects has attracted the attention of additional clinical and non-clinical populations, including athletes. Unlike the intoxicating cannabinoid, Δ 9 -tetrahydrocannabinol (Δ 9 -THC), CBD is no longer prohibited by the World Anti-Doping Agency and appears to be safe and well-tolerated in humans. It has also become readily available in many countries with the introduction of over-the-counter “nutraceutical” products. The aim of this narrative review was to explore various physiological and psychological effects of CBD that may be relevant to the sport and/or exercise context and to identify key areas for future research. As direct studies of CBD and sports performance are is currently lacking, evidence for this narrative review was sourced from preclinical studies and a limited number of clinical trials in non-athlete populations. Preclinical studies have observed robust anti-inflammatory, neuroprotective and analgesic effects of CBD in animal models. Preliminary preclinical evidence also suggests that CBD may protect against gastrointestinal damage associated with inflammation and promote healing of traumatic skeletal injuries. However, further research is required to confirm these observations. Early stage clinical studies suggest that CBD may be anxiolytic in “stress-inducing” situations and in individuals with anxiety disorders. While some case reports indicate that CBD improves sleep, robust evidence is currently lacking. Cognitive function and thermoregulation appear to be unaffected by CBD while effects on food intake, metabolic function, cardiovascular function, and infection require further study. CBD may exert a number of physiological, biochemical, and psychological effects with the potential to benefit athletes. However, well controlled, studies in athlete populations are required before definitive conclusions can be reached regarding the utility of CBD in supporting athletic performance.

Key Points

CBD has been reported to exert a number of physiological, biochemical, and psychological effects that have the potential to benefit athletes.

The available evidence is preliminary, at times inconsistent, and largely based on preclinical studies involving laboratory animals.

Rigorous, controlled investigations clarifying the utility of CBD in the sporting context are warranted.

Introduction

Cannabis sativa contains numerous chemical compounds with potential bioactive effects, including at least 144 cannabinoids [56, 76]. The most studied of the cannabinoids are Δ 9 -tetrahydrocannabinol (Δ 9 -THC), renowned for its distinctive intoxicating effects [73, 123], and cannabidiol (CBD)—a non-intoxicating cannabinoid that is particularly enriched in industrial hemp cultivars grown for seed and fibre [61]. CBD was first isolated in 1940 and initially considered to be biologically inactive, with no apparent therapeutic or “subjective” drug effects [1]. However, in 1973, Carlini et al. [27] demonstrated anticonvulsant effects of CBD in a preclinical model, which were later mirrored in humans suffering from intractable epilepsy [46]. A subsequent rise in research into CBD [206] has uncovered interactions with numerous molecular targets [92] and a range of potential therapeutic applications [138]. Following successful phase 3 clinical trials [53, 54, 172], the oral CBD solution, Epidiolex®, has also recently gained Food and Drug Administration approval as a regulated prescription medication to treat certain forms of paediatric epilepsy.

Recently, interest in CBD has intensified among the general population as evidenced by an exponential rise in internet searches for ‘CBD’ in the United States (USA) [108]. Some professional athletes (e.g. golfers, rugby players) also appear to be using CBD (e.g. ‘Team cbdMD’ https://www.cbdmd.com/), despite there being no published studies demonstrating beneficial effects on sport or exercise performance. In many jurisdictions, including the USA and Europe, access to regulated, prescription CBD (i.e. Epidiolex®) is limited to patients with intractable epilepsy. However, a wide range of low dose (e.g. 5–50 mg·d −1 ) CBD-containing “nutraceuticals” (primarily in oil or capsule form) have become readily available online and over-the-counter (e.g. pharmacies, health food stores) [20, 125]. This includes some varieties that are marketed specifically to recreational and elite athletes (e.g. cbdMD, fourfivecbd). The use of these products is likely to become even more widespread if the World Health Organization’s recommendation that CBD no longer be scheduled in the international drug control conventions is adopted by the United Nations member states [201].

Cannabis has been prohibited in all sports during competition since the World Anti-Doping Agency first assumed the responsibility of establishing and maintaining the list of prohibited substances in sport 15 years ago [89]. In 2018, however, CBD was removed from the Prohibited List [199], presumably on the basis of mounting scientific evidence that the cannabinoid is safe and well-tolerated in humans [16, 169], even at very high doses (e.g. 1500 mg·day −1 or as an acute dose of 6000 mg) [170]. While several recent reviews have described the impact of cannabis on athlete health and performance [99, 176, 188], the influence of CBD alone has yet to be addressed.

The aim of this narrative review was to explore evidence on the physiological, biochemical, and psychological effects of CBD that may be relevant to sport and/or exercise performance and to identify relevant areas for future research. Given the absence of studies directly investigating CBD and sports performance, this review draws primarily on preclinical studies involving laboratory animals and a limited number of clinical trials involving non-athlete populations.

Cannabidiol (CBD): Molecular Targets, Pharmacokinetics and Dosing

Molecular Targets

The distinctive intoxicating effects of Δ 9 -THC (as well as some of its therapeutic effects) involve the activation of CB1R (the cannabinoid type 1 receptor) [12]. This ubiquitous receptor is expressed throughout the central nervous system, the peripheral nervous system, and in the cardiovascular system, gastrointestinal (GI) tract, skeletal musculature, liver, and reproductive organs [205]. Unlike Δ 9 -THC, CBD is not an agonist of CB1R, although it may act as a negative allosteric modulator (NAM) at this site (i.e. decreasing the potency and/or efficacy of other ligands without activating the receptor itself) [92, 106]. Δ 9 -THC also acts as an agonist at CB2R (the cannabinoid type 2 receptor) [12] and there is emerging evidence of CBD functioning as a partial agonist at this site [171]. CB2R is primarily located on immune system cells but is also expressed in the cardiovascular system, GI tract, bone, liver, adipose tissue, and reproductive organs [205]. CBD may also influence the endocannabinoid system indirectly via the inhibition of fatty acid amide hydrolase (FAAH), a key enzyme involved in the degradation of the principle endocannabinoid signalling molecule, anandamide (AEA) [92, 110]. The inhibition of FAAH is predicted to lead to an increase in brain and plasma concentrations of AEA, which acts as a partial agonist at CB1R and CB2R, thereby increasing endocannabinoid tone [92, 110]. Increases in endocannabinoid tone may also occur as a result of CBD inhibiting AEA transport via effects on fatty acid-binding proteins (and this mechanism may have more relevance than FAAH inhibition in humans) [57].

CBD also interacts with many other non-endocannabinoid signalling systems [92]. Briefly, at concentrations ≤ 10 μM, CBD has been reported to interact with the serotonin 1A [5-HT1A] receptor, the orphan G protein-coupled receptor 55, as well as the glycine, opioid, and peroxisome proliferator-activated receptors, various ion channels (e.g. the transient potential vanilloid receptor type 1 channel [TRPV1] and other transient potential vanilloid channels) and various enzymes (e.g. cyclooxygenase (COX)1 and COX2, cytochrome P450 enzymes) [11, 92] (see Ibeas et al. [92] for review). CBD also possesses antioxidant properties [92].

It is important to recognise that the molecular targets of CBD are still being established, with many of those identified in in vitro cellular assays still to be validated as occurring in vivo. As such, the functional relevance of many of these interactions remains to be established.

Pharmacokinetics

CBD is often consumed orally as oil; however, it can also be ingested in other forms (e.g. gel capsules, tinctures, beverages, and confectionery products) and applied topically [20, 125]. High concentration CBD “vape oils” (i.e. for use in e-cigarette devices) are also available in some countries, as are some CBD-dominant forms of cannabis (sometimes known as “light cannabis”) that can be smoked or vaporised [20, 125]. Pure, synthetic, crystalline CBD was also vaporised in a recent laboratory study [160].

Taylor et al. [170] recently conducted a comprehensive analysis of oral CBD oil pharmacokinetics in healthy participants. When administered as a single, oral dose (1500–6000 mg), the time to reach peak plasma concentrations (tmax) was ~4–5 h and the terminal half-life was ~14–17 h. Although tmax did not increase dose-dependently in this investigation [170], another study [19], involving a much lower oral dose of CBD (300 mg), did indicate a shorter tmax (i.e. ~2–3 h). Peak plasma concentrations (Cmax) were ~0.9–2.5 μM in Taylor et al. [170], but increased ~4.9-fold when CBD was administered with a high-fat meal (i.e. ~5.3 μM at 1500 mg dose) [170]. Both studies observed a large amount of inter-individual variation in pharmacokinetic responses [19, 170].

The pharmacokinetics of inhaled CBD are yet to be well characterised. However, smoked “light cannabis” (with a lower Δ 9 -THC and higher CBD content than other varieties) has been reported to elicit high serum CBD concentrations at 30 min post-treatment (that decline over time) [146]. A recent study in which participants vaporised 100 mg of CBD likewise observed high blood CBD concentrations 30 min post-treatment [160]. As neither study collected blood samples within < 30 min of CBD administration, tmax and Cmax are unknown [146, 160].

CBD is metabolised by several cytochrome P [CYP] 450 enzymes (e.g. CYP3A4, CYP2C9, CYP2C19) which convert it to a number of primary and secondary metabolites (e.g. 7-OH-CBD, 6-OH-CBD, and 7-COOH-CBD) [177]. Complex pharmacokinetic interactions may occur when CBD is co-administered with other drugs (e.g. Δ 9 -THC) and dietary constituents (e.g. caffeine) that also utilise these enzymes [6, 163].

Interspecies Dose Conversions

Given the number of preclinical studies involving animal models that will be discussed in this review, it is important to consider interspecies dose equivalence (Table ​ (Table1). 1 ). The USA Food and Drug Administration [30] recommend the following approach to interspecies dose conversion:

Table 1

Oral human equivalent CBD doses from mouse and rat intraperitoneal doses

Mouse to Human CBD Dose Conversion Rat to Human CBD Dose Conversion
Mouse Dose
(mg·kg -1 , i.p.)
HED
(mg, p.o.)
Rat Dose
(mg·kg -1 , i.p.)
HED
(mg, p.o.)
1 34 1 68
5 170 5 340
10 341 10 681
20 681 20 1362
30 1021 30 2043
60 2043 60 4086

Each HED is based on a body mass of 60 kg and calculated as per the methods described in 2.3 Dose Conversions. The highest documented acute oral CBD dose in humans is 6000 mg; the highest documented chronic oral CBD dose in humans is 1500 mg [169]. HED: Human Equivalent Dose; i.p.: Intraperitoneal; p.o.: Oral

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Where HED is the human equivalent dose and Km is a correction factor estimated by dividing the average body mass (BM) of the species (60, 0.020 and 0.150 kg for 11 humans, mice and rats respectively) and by its surface area (see: Nair, et al. [134] for 12 further details).

Differences between systemic and oral dosing should also be considered [9]. Intraperitoneal (i.p.) dosing is often used in animal studies and has been reported to elicit Cmax values ~7-fold higher than oral dosing in mice [52]. Thus, an “oral equivalent dose” can be approximated by multiplying the i.p. dose by seven [9] (Table ​ (Table1). 1 ). Intravenous (i.v.) dosing will produce even higher plasma CBD concentrations; however, the authors are not aware of any published data that would facilitate conversion between i.v. and oral dosing in rodents. Please note that these values are intended as a guide only and subject to limitations (e.g. interspecies differences in drug potency and receptor expression/configuration).

Cannabidiol (CBD) in Sport and Exercise Performance

Literature Search Methodology

The clinical and preclinical literature was reviewed to identify studies investigating the effects of CBD that might be relevant within a sport and/or exercise context. The online databases PubMed (MEDLINE), Web of Science (via Thomas Reuters), and Scopus were searched between April and October of 2019 using terms such as: ‘cannabinoid’ ‘cannabidiol’, ‘CBD’ and ‘cannabis’. This review focuses primarily on effects that have been demonstrated in vivo and generally avoids attempting to predict functional effects on the basis of target-oriented in vitro data, given the numerous molecular targets of CBD [92] and the fact that exercise itself induces complex biochemical changes. Nonetheless, some potential interactions are noted. As our intent was to summarise evidence on a range of potentially relevant topics, rather than provide a detailed assessment of the literature, the reader will be directed to more focused reviews, where appropriate. All doses described are oral and acute (single), unless otherwise stated.

Exercise-Induced Muscle Damage—Muscle Function, Soreness, and Injury

Exercise, particularly when strenuous, unfamiliar, and/or involving an eccentric component, can cause ultrastructural damage to skeletal muscle myofibrils and the surrounding extracellular matrix [36, 59]. This exercise-induced muscle damage (EIMD) impairs muscle function and initiates an inflammatory response [59]. While inflammation is integral to EIMD repair, regeneration, and adaptation [59], excessive inflammation may contribute to prolonged muscle soreness and delayed functional recovery [7, 158].

CBD modulates inflammatory processes [21]. In preclinical models of acute inflammation, CBD has been reported to attenuate immune cell accumulation (e.g. neutrophils, lymphocytes macrophages) [102, 130, 149, 186], stimulate production of anti-inflammatory cytokines (e.g. interleukin (IL)-4, IL-10) [190, 191, 23] and inhibit production of pro-inflammatory cytokines (e.g. IL-1β, IL-6, IL-8, tumour necrosis factor (TNF)-α) [10, 50, 55, 62, 63, 113, 130, 149, 154, 186] and reactive oxygen species [62, 130, 186]. Models demonstrating such effects have included lung injury induced by chemical treatment [149] and hypoxic–ischemia (HI) [10]; liver injury induced by ischemia-reperfusion [63, 130] and alcohol feeding [186]; myocardial [55] and renal [62] ischemia-reperfusion injuries; surgically induced oral lesions [102]; chemically induced osteoarthritis [145]; spinal cord contusion injury [113], and colitis [23, 50, 154] (see Burstein [24] for review). Anti-inflammatory effects are generally observed at higher CBD doses in vivo (e.g. ≥ 10 mg·kg −1 , i.p.); although, lower doses (e.g. ~1.5 mg·kg −1 , i.p.) have indicated efficacy in some studies [145]. Research investigating the effects of CBD on inflammation in humans is limited and inconclusive [94, 133].

In terms of muscle-specific inflammation, one preclinical study has investigated the effect of high-dose CBD (i.e. 60 mg·kg −1 ·d −1 , i.p.) on transcription and synthesis of pro-inflammatory markers (i.e. IL-6 receptors, TNF-α, TNF-β1, and inducible nitric oxide synthase) in the gastrocnemius and diaphragm of dystrophic MDX mice (a mouse model of Duchenne muscular dystrophy) [91]. In this investigation, CBD attenuated mRNA expression of each marker and reduced plasma concentrations of IL-6 and TNFα. Improvements in muscle strength and coordination, as well as reductions in tissue degeneration, were also reported at this dose. Lower, but still relatively high, CBD doses (20–40 mg·kg −1 ·day −1 , i.p.) had no functional benefits [91]. Of course, it is important to recognise that EIMD and muscular dystrophy differ in their pathophysiology, and so the effects observed in MDX mice may involve mechanisms less relevant to EIMD (e.g. skeletal muscle differentiation, autophagy) [91].

While CBD could potentially aid in muscle recovery, other anti-inflammatory agents, such as ibuprofen (a non-steroidal anti-inflammatory drug [NSAID]) have been reported to attenuate exercise-induced skeletal muscle adaptation [120]. The precise mechanism(s) underpinning these effects have not been fully elucidated, although it may be that the prevention of inflammation inhibits angiogenesis and skeletal muscle hypertrophy [120]. Human trials also suggest that ibuprofen may not influence EIMD, inflammation, or soreness [144, 175]. Thus, if CBD exerts its effects via similar mechanisms, it could possibly attenuate the benefits of training without influencing muscle function or soreness. Future studies investigating this are clearly warranted to clarify such issues and elucidate the potential benefits of CBD.

Neuroprotection—Concussion and Subconcussion

Recent estimates suggest that 6–36% of high school and collegiate athletes in the USA have experienced more than one concussion [72], potentially predisposing them to long-term neurodegenerative diseases [72] and an increased risk of suicide [64]. Concussion is a distinct form of mild traumatic brain injury (TBI) in which a biomechanical force temporarily disrupts normal brain functioning causing neurological–cognitive–behavioural signs and symptoms [97]. Similar injuries that do not produce overt (acute) signs or symptoms are termed “subconcussions” [97]. In TBI, the primary injury occurs as a result of the biomechanical force; secondary injury is then sustained through a complex cascade of events, including HI, cerebral oedema, increased intracranial pressure, and hydrocephalus [203]. These processes are, in turn, related to a number of detrimental neurochemical changes, including glutamate excitotoxicity, perturbation of cellular calcium homeostasis, excessive membrane depolarisation, mitochondrial dysfunction, inflammation, increased free radicals and lipid peroxidation, and apoptosis [203]. While the primary injury may not be treatable, interventions that attenuate secondary sequelae are likely to be of benefit [203].

Only one study [14] has investigated the biochemical and neuropsychological effects of CBD in an animal model of TBI. Here, C57BL/6 mice were given chronic CBD treatment (3 μg·day −1 , oral) 1–14 and 50–60 days post- (weight drop) brain insult. CBD attenuated the behavioural (e.g. anxious and aggressive behaviour, depressive-like behaviour, impaired social interactions, pain-related behaviours) and some of the cortical biochemical abnormalities were observed. Specifically, CBD tended to normalise extracellular glutamate, d -aspartate, and γ-aminobutyric acid concentrations in the medial prefrontal cortex, suggesting a reduction in excitotoxicity. However, neuronal damage was not measured directly in this study [14].

Other preclinical studies have investigated the impact of CBD on different animal models of acute neuronal injury, in particular, acute cerebral HI [4, 13, 31, 68, 69, 80, 81, 83, 100, 105, 127, 129, 142, 143, 153]. Studies administering a single (acute) dose of CBD shortly post-HI (e.g. ≤1 h) have produced inconsistent results. For instance, while Garberg et al. [68, 69] found no effect of CBD (1 or 50 mg·kg −1 , i.v.) on HI-induced neuronal damage in piglets, others observed neuroprotection at similar doses (e.g. 1 mg·kg −1 , i.v [105, 143]., 1 mg·kg −1 , s.c [127, 142]., and 5 mg·kg −1 , i.p [31].) in piglets and rats. When given chronically, or repeatedly within a short timeframe proximal to the HI event, however, CBD appears to be neuroprotective. Effective dosing strategies have varied and included initiating treatment several days pre-HI (e.g. 100 or 200 μg·day −1 , intracerebroventricular 5 days; Wistar rats [100]), shortly pre- and/or post-HI 1 , and up to 3 days post-HI (e.g. 3 mg·kg −1 ·day −1 , i.p. 12 days; ddY mice [80]). Thus, chronic CBD treatment may be more effective than acute intervention. While “pre-incident” dosing might also be beneficial, it is noted that in practice, this would require humans at risk of TBI to use CBD chronically as a prophylactic.

The precise mechanism(s) underpinning the neuroprotective effects of CBD are not completely understood (see Campos et al. [25] for review), but may involve decreased inflammation, oxidative stress, and excitotoxicity [142, 143] and increased neurogenesis [129]. Preclinical studies have also demonstrated beneficial effects of CBD in other animal models of neurodegeneration (e.g. transgenic model of Alzheimer’s disease [34, 35], brain iron-overload [47, 48]). Collectively, these data suggest that research investigating the utility of CBD in ameliorating the harmful long-term effects of repeated sports concussions is warranted.

Nociceptive and Neuropathic Pain

Persistent pain is common in athletes [74]. Nociceptive pain, which includes inflammatory pain, typically occurs with tissue damage; whereas neuropathic pain typically results from a lesion or disease in the somatosensory nervous system [74]. Neuropathic pain is common among para-athletes with spinal cord injuries and can also arise with surgery (e.g. to treat an existing injury) or if there is repetitive mechanical and/or inflammatory irritation of peripheral nerves (e.g. as in endurance sports) [74].

Clinical trials investigating the combined effects of Δ 9 -THC and CBD (e.g. Sativex®) on chronic neuropathic pain have yielded promising initial results [87, 114, 151, 156]. However, the therapeutic effects of CBD administered alone have received limited clinical attention. Preclinical (in vivo) studies investigating the effects of CBD on neuropathic and nociceptive pain are summarised in Table ​ Table2. 2 . Despite some methodological inconsistencies (e.g. the pain model, period of treatment, route of delivery), most preclinical studies appear to have observed a significant analgesic effect of CBD [29, 39–41, 51, 70, 75, 78], albeit somewhat less pronounced than the effects of Δ 9 -THC [29, 78] (e.g. Hedges’ g = 0.8 vs. 1.8 [78]) or of gabapentin (e.g. Hedges’ g = 2.0 [78]), a commonly used agent for treating neuropathic pain. Capsazepine co-treatment has also been reported to attenuate CBD-induced analgesia, suggesting that the effect may be mediated, at least in part, by the TRPV1 channel [40, 41, 51]. This mechanism is noteworthy as studies have implicated the TRPV1 in the development of mechanical hyperalgesia induced by muscle inflammation [66, 140].

Table 2

Preclinical studies investigating the effect of CBD on neuropathic and nociceptive pain in vivo

Citation Animal Model Treatment(s) Treatment Effect
Neuropathic Pain
De Gregorio et al., (2019) [51] Wistar rats SNI 5 mg·kg -1 ·d -1 , s.c. 7 d CBD sig. decreased mechanical allodynia on Tx day 7.
Casey et al., (2017) [29] C57BL/6 mice CCI 30 mg·kg -1 , s.c. CBD sig. decreased mechanical allodynia 2 h, but not 0.5, 1, 4 or 6 h, post-Tx compared to baseline.
0.01, 0.1, 1, 10 or 100 mg·kg -1 , s.c. CBD dose-dependently decreased mechanical and cold allodynia.
King et al., (2017) [101] C57BL/6 mice CT (Paclitaxel) 0.625–20 mg·kg -1 , i.p. 15 min prior to CT on days 1, 3, 5 and 7 1 and 20 mg·kg -1 CBD sig. attenuated the development of mechanical allodynia measured on Tx days 9 and 14, but not 21.
CT (Oxaliplatin) 1.25–10 mg·kg -1 , i.p. 15 min prior to CT on days 1, 3, 5 and 7 1.25–10 mg·kg -1 CBD sig. attenuated the development of mechanical allodynia measured on Tx days 2, 4, 7 and 10.
CT (Vincristine) 1.25–10 mg·kg -1 , i.p. 15 min prior to CT on days 1, 3, 5 and 7 CBD did not attenuate the development of CT-induced mechanical allodynia measured on Tx days 5, 10, 15 and 22.
Harris et al., (2016) [78] C57BL/6 mice CT (Cisplatin) 2 mg·kg -1 , i.p. CBD sig. decreased tactile allodynia 1 h post-Tx.
0.5, 1 or 2 mg·kg -1 , i.p. 30 min prior to CT every second day for 12 d CBD did not attenuate the development of CT-induced tactile allodynia measured on Tx days 6, 10 and 12.
Ward et al., (2014) [187] C57BL/6 mice CT (Paclitaxel) 2.5 or 5 mg·kg -1 ·d -1 , i.p. 15 min prior to CT on days 1, 3, 5 and 7 2.5 and 5 mg·kg -1 ·d -1 CBD attenuated the development of CT-induced mechanical allodynia.
Toth et al., (2010) [174] CD1 mice STZ Diabetes 0.1, 1 or 2 mg·kg -1 ·d -1 , i.n. 3 months 1 and 2 mg·kg -1 ·d -1 CBD sig. attenuated the development of thermal and tactile hypersensitivity compared to 0.1 mg·kg -1 ·d -1 CBD.
2 mg·kg -1 ·d -1 , i.n. 1 month CBD did not alleviate developed thermal or tactile hypersensitivity.
1, 10 or 20 mg·kg -1 ·d -1 , i.p. 3 months 20 mg·kg -1 ·d -1 CBD sig. attenuated the development of thermal and tactile hypersensitivity compared to 1 mg·kg -1 ·d -1 CBD.
20 mg·kg -1 ·d -1 , i.p. 1 month CBD did not alleviate developed thermal or tactile hypersensitivity.
Costa et al., (2007) [41] Wistar rats CCI 2.5, 5, 10 or 20 mg·kg -1 ·d -1 , oral 7 d 5, 10 and 20 mg·kg -1 ·d -1 CBD sig. decreased thermal and mechanical hyperalgesia on Tx day 7.
Nociceptive (Inflammatory) Pain
Genaro et al., (2017) [70] Wistar rats Incision 0.3, 1, 3, 10 or 30 mg·kg -1 , i.p. 3 mg·kg -1 CBD sig. decreased mechanical allodynia between 30- and 150-min post-Tx; 10 mg·kg -1 CBD sig. decreased mechanical allodynia 60 min post-Tx, only.
Hammell et al., (2016) [75] Sprague-Dawley rats FCA 0.6, 3.1, 6.2 or 62.3 mg·kg -1 ·d -1 , t.c. 4 d 6.2 and 62.3 mg·kg -1 CBD sig. decreased pain-related behaviour on Tx day 4 and thermal hyperalgesia on Tx days 2, 3 and 4.
Costa et al., (2007) [41] Wistar rats FCA 20 mg·kg -1 ·d -1 , oral 7 d CBD sig. decreased thermal and mechanical hyperalgesia on Tx day 7.
Costa et al., (2004) [39] Wistar rats Carrageenan 5, 7.5, 10, 20 and 40 mg·kg -1 , oral 5, 7.5, 10, 20 and 40 mg·kg -1 ·d -1 CBD sig. decreased thermal hyperalgesia 1–5 h post-Tx.
Costa et al., (2004) [40] Wistar rats Carrageenan 10 mg·kg -1 , oral CBD sig. decreased thermal hyperalgesia 1 h post-Tx.
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The ‘Treatment Effects’ described are in comparison to a vehicle condition, unless otherwise stated

CBD Cannabidiol, CCI Chronic Constriction Injury, CT Chemotherapy, FCA Freund’s Complete Adjuvant, i.n. Intranasal, i.t. Intrathecal, s.c. Subcutaneous, SNI Spared Nerve Injury, STZ Streptozotocin, t.c. Transcutaneously, Tx Treatment

It is important to recognise that the analgesic effect of CBD likely depends on several factors, including the treatment dose and the type of pain involved. Indeed, low doses of CBD (e.g. ≤ 1 mg·kg −1 , i.p.) do not consistently attenuate pain [29, 41, 70, 75, 101]; while higher doses are sometimes found to be more [29], and other times, less [70], efficacious than moderate doses in preclinical studies (Table ​ (Table3). 3 ). This highlights the importance of determining a therapeutic dose for CBD in analgesia. Data from King et al. [101] also demonstrate the selectivity of the response, indicating that CBD only effective in attenuating the development of neuropathic pain induced by certain chemotherapeutic agents (i.e. paclitaxel and oxaliplatin but not vincristine). Thus, placebo-controlled trials of CBD in treating pain in clinical populations and athletes are warranted.

Potential Role of Cannabidiol on Sports Recovery: A Narrative Review

This is an open-access article distributed under the terms of the Creative Commons Attribution License (CC BY). The use, distribution or reproduction in other forums is permitted, provided the original author(s) and the copyright owner(s) are credited and that the original publication in this journal is cited, in accordance with accepted academic practice. No use, distribution or reproduction is permitted which does not comply with these terms.

Abstract

The use of cannabidiol (CBD) among athletes is becoming extensive and frequent. This could be due to the elimination of CBD from the list of prohibited substances by federations and international institutions of sport. The legalization and resulting production, and commercialization of CBD, could increase its intake in sports professionals. This commercialization of cannabinoids has fueled a race to study their properties, benefits, and risks for health and performance in athletes. Although there is evidence that suggests some beneficial properties such as anxiolytics, antidepressants, anti-inflammatory, and antioxidants among others, the evidence presented so far is neither clear nor conclusive. There are significant gaps in knowledge of the physiological pathways that explain the role of CBD in sports performance. This mini-review examines evidence suggesting that CBD has the potential to be used as a part of the strategies to recover from fatigue and muscle damage related to physical and cognitive exertion in sports.

Introduction

Recovery has become a crucial topic in recent sports research and could determine physical (Trecroci et al., 2020b), physiological (Rojas-Valverde et al., 2018), and cognitive (Trecroci et al., 2020a) performance, considering the high frequency and density of competitions. This has led the researchers, coaches, and athletes making plans and managing recovery strategies as part of the general exercise prescription (Martínez-Guardado et al., 2020). The physical, physiological, and cognitive effort usually provoke a cascade of structural and functional adjustments that need to be identified, monitored, and controlled to optimally recover the functional capacities of the athlete (Ament and Verkerke, 2009). Commonly, central and peripheral fatigue related to physical exercise manifests itself as pain, weakness, inflammation, loss of functional mobility, decreased force generation, feeling of tiredness, alteration of vital signs, and reduced concentration, among others.

Over the last few years, many methods and means of recovery from fatigue have been tested (Rawson et al., 2018). One of the best known strategies is the intake of plant-derived products such as ginseng (Rojas-Valverde et al., 2020), green tea (Machado et al., 2018), cherries (Bell et al., 2014), curcumin (Fernández-Lázaro et al., 2020), spinach (Bohlooli et al., 2014), and beetroot (Rojas-Valverde et al., 2020). These organic products have shown anti-inflammatory, antioxidative, and analgesic properties as other cognitive benefits that promote recovery from exercise-related fatigue (Bongiovanni et al., 2020).

Recently, the World Anti-Doping Agency has removed some products from their list of prohibited substances for athletes. This is the case of cannabidiol (CBD), a phytocannabinoid clustered among the cannabinoids extracted from the Cannabis sativa plant (Campos et al., 2012). Unlike tetrahydrocannabinol (THC), CBD does not cause psychotomimetic and psychotropic reactions (WHO, 2017) for which there is no evidence of dependence or abuse, but causes mild and infrequent side effects (Stout and Cimino, 2014). On the contrary, CBD use is not only extensive among athletes (Docter et al., 2020), but it has been shown to have specific properties that help to treat chronic pain, spasticity, mood and sleep disorders, immunodepression, inflammation, oxidant effects, and anxiety in clinical patients (McPartland et al., 2015; Whiting et al., 2015; Nichols and Kaplan, 2019; Pinto et al., 2020). These effects could improve and accelerate recovery caused by a prolog or intense physical, physiological, and cognitive efforts as in sports (Higgins et al., 2017).

Considering that CBD has gained wide acceptance for medicinal and recreational use, its use among athletes is imminent (Docter et al., 2020) even though its the physiological, physical, and cognitive effects are not fully understood (Nichols and Kaplan, 2019), and it seems premature to make specific recommendations and to award all the above mentioned benefits (Gamelin et al., 2020). Consequently and considering the need to clarify these issues, this narrative review aims to present the scientific evidence around the potential benefits of CBD as an ergogenic aid to promote a better and faster recovery between efforts related to physical exercise and sport. Given the absence of evidence directly exploring the CBD potential in sports recovery, this review synthesizes the preclinical and clinical findings that support its use and testing in future research protocols. This narrative review was performed considering the scale for assessment of narrative review articles (Baethge et al., 2019).

Prevalence in the Use of CBD Among Athletes

With the exclusion of CBD from the prohibited substances in 2018, and even before, the use of CBD among athletes has considerably increased and is still accelerating (Leas et al., 2019). Cannabinoids are considered the second most commonly used substance among contact sports athletes replacing nicotine (McDuff et al., 2019). Evidence has shown that a third of cyclists, triathletes, and runners are or have been cannabinoids users (mostly ≥ 40 years of age, male, THC + CBD consumers ≤3 times weekly, and exercise 5–7 days per week) (Zeiger et al., 2019). Also, a quarter of university athletes report using cannabis-related products (Docter et al., 2020). Especially in contact sports like rugby, the use rate of CBD is 28%, increasing with age, and reporting pain relief and sleep quality improvements as perceived benefits (Kasper et al., 2020).

Despite the extensive use of CBD and the fact that international sports organizations have now allowed for it to be used, some CBD products have been shown to contain significant levels of other banned cannabinoids, like THC (Lachenmeier and Diel, 2019). Besides, there is evidence of the use of synthetic cannabinoids, such as JWH-018 and JWH-073, with limited regulation (Heltsley et al., 2012). Athletes require more information and advice, as product labels can be misleading about whether they contain THC, meaning there are risks in terms of violating anti-doping rules (Mareck et al., 2021).

Physiological Mechanism Framing CBD

The effects of CBD on physiological and cognitive functions are mediated by the endocannabinoid system, which has regulatory functions to maintain homeostasis (VanDolah et al., 2019). During exercise, the cannabinoid system mediates some central and peripheral effects of exercise as bliss, peacefulness, and euphoria (Carek et al., 2011). Endocannabinoids [e.g., anandamide and 2-arachidonyol (2AG)] as cannabinoids activate the type-1 (CB1) and type-2 (CB2) cannabinoid receptors, such as N-acylethanolamines (De Petrocellis and Di Marzo, 2009), leading to appetite-suppression, anti-inflammatory, anxiolytic, and antiproliferative effects as exercise do. CBD inhibits the degradation and uptake of endocannabinoids as anandamide, leading to an increase in endocannabinoid–receptor binding. CB1 and CB2 are present mostly in the central nervous and peripheric nervous system, respectively.

Also, cannabinoids and endocannabinoids are involved in brain-derived neurotrophic factor release (e.g., neurogenesis and neuronal plasticity), glucocorticoids release (e.g., mood control by suppressing depression and anxiety), dopamine release (leading to rewarding), and fatty acid amide hydrolase release (e.g., analgesic effects). All these responses overlap with the positive benefits of exercise (Tantimonaco et al., 2014). These effects are provoked by stimuli of TRPV1 ions canals (Vanilloid receptors) leading to antinociceptive effects, stimuli of CB1 and CB2 receptors causing relaxing effects via neurodepression and inhibition of cytokines release, respectively, and activation of 5HT1A receptors promoting serotonin caption in the postsynaptic neuron causing mood state regulation.

Inflammation and Proliferation

Inflammation and oxidative stress underlie many human chronic and acute health conditions and pathologies. In this sense, and considering that exercise-related damage and fatigue mediate inflammation, proliferation, and oxidative stress in most cases, it is hypothesized that CBD-related inhibitions in oxidative stress and neuroinflammation could have some therapeutic potential in sports research (Gamelin et al., 2020). This statement is based on evidence suggesting that CBD could induce changes in cortisol release, regulating inflammatory response to injury (Zuardi A. et al., 1993; Yeager et al., 2010). This mediation is due to the interaction between CBD CB1, and CB2 cannabinoids and adenosine receptors, leading to reduced cytokine levels and downregulating overreactive immune cells (Booz, 2011; Hill et al., 2012; Burstein, 2015). Also, CBD intake seems to mediate processes associated with gastrointestinal damage protection, due to inflammation, and promote healing of skeletal injuries (McCartney et al., 2020).

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During exercise, mainly those actions with a high component of eccentric contraction are potentially and particularly damaging to the sarcolemma. This damage is fetterless in response to a disruption of the permeability of muscle cell membrane and basal lamina, allowing Ca 2 + to reduce fiber electrochemical gradient. If the damage in the sarcolemma is relatively low, ATPase pumps attract Ca 2+ and the damage is still reversible. Besides, if there is a Ca 2+ overload, a degradation of the structural and contractile proteins could be provoked. The subsequent event is called the inflammatory cascade, recognized by the activation of macrophages and other phagocytic cells during the first 2–6 h after injury and prolonged for days (Armstrong et al., 1991; Burstein, 2015).

Additionally, CBD (300 mg) has been shown to induce changes in glucocorticoids as cortisol in humans (Zuardi A. W. et al., 1993), one of the primary homeostatic regulators of the inflammatory response to injury (Yeager et al., 2010). This is supported by a recent narrative review in sports, suggesting the potential anti-inflammatory effect in humans and the possible role in the performance of the athletes (McCartney et al., 2020). This affirmation is theoretically based on the suggested CBD capacity to interact with receptors involved in controlling inflammation as CB1 cannabinoid, CB2 cannabinoid, adenosine A2A, and also in reducing the levels of some cytokines, such as interleukin-1 (IL-1) and tumor necrosis factor α (TNFα), and downregulating overreactive immune cells reducing the impact of collateral inflammatory damage of tissues (Booz, 2011; Hill et al., 2012; Burstein, 2015). There is also evidence suggesting the CBD potential to promote the release of arachidonic acid, leading to greater healing capacity as a result of core regulation of growth signals mediated by proresolving substances, such as lipoxin A4 and 15d-PGJ2 (Burstein, 2015).

It is also known that the interplay between inflammation and oxidative stress underlies many human diseases due to tissue and organ damage. In this regard, in sports, it is hypothesized that CBD-related inhibitions in oxidative stress and neuroinflammation could have some therapeutic potential in sports research (Gamelin et al., 2020).

Pain and Soreness

Cannabidiol has been commonly used for its analgesic properties (Kogan and Mechoulam, 2007) in a variety of pain disorders (Starowicz and Finn, 2017). CBD consumption could exhibit a beneficial effect over edema and hyperalgesia (Burstein, 2015; Hill et al., 2017), acting directly on the central nervous system and leading to sedative effects (Zuardi A. W. et al., 1993). The idea of considering CBD as an antinociceptive agent is based on the efficiency of treating the pain associated with proinflammatory cytokine release due to the activation of Vanilloid receptors, provoking antinociceptive effects and reducing the perception of pain (Booz, 2011). CBD could inhibit presynaptic neurotransmitters and neuropeptide release, modulate postsynaptic neuronal excitability, activate the descending inhibitory pain pathway, and reduce neuroinflammatory signaling (Starowicz and Finn, 2017).

Cannabidiol (300–400 mg) intake seems to have sedative effects on humans apparently acting directly on the central nervous system (Zuardi A. W. et al., 1993), supported by the idea that CBD exhibited a beneficial action over edema and hyperalgesia (Burstein, 2015; Hill et al., 2017). In this regard, drugs and substances such as Sativex, THC, and CBD are approved for the treatment of both central and peripheral neuropathic pain. This pain syndrome is associated with microglia activation and subsequent cascade of proinflammatory cytokines such as IL-6, IL-1β, and TNF (Booz, 2011). This evidence supports the idea of CBD use as an antinociceptive agent. Together with a neuroprotective quality, this effect was also found in a recent systematic review on the outcome of CBD intake in relation to its potential use as a sport-enhancing performance substance (McCartney et al., 2020). It still is unclear how CBD acts in relation to the pain cascade and pathways (Anthony et al., 2020). CBD has shown its potential to treat and manage pain in diseases and pain disorders, and based on this evidence CBD seems to have a potential effect on treating swelling and preventing soreness after strenuous exercise, but more evidence is required to make a clear statement.

Sleep Disorders

Overreaching and overtraining are often presented in athletes due to high training loads accompanied by subsequent insufficient recovery between efforts (Fox et al., 2020). These abovementioned states are usually accompanied by sleep disorders and higher sleep disturbance, leading to poor sleep quality (Hainline et al., 2017). CBD consumption could stimulate the endocannabinoid system modulating sleep disorders and the sleep–wake cycle (Murillo-Rodríguez et al., 2020). Promising, but no specific, evidence suggests using cannabinoids like CBD to reduce sleep disorders in athletes or even in healthy or pathologic humans. Endocannabinoid system receptors as anandamide and type-1 are associated with sleep-promoting effects, but the physiological mechanism is not fully understood and is based mainly on preclinical studies (Suraev et al., 2020).

Cognition and Mood

Evidence has shown that acute and single administration of CBD could have anxiolytic (Zuardi A. et al., 1993) and antidepressive effects through the activation of 5-HT1A receptors (Booz, 2011). Although the reported results are promising for sports recovery, evidence suggests no long-term impact on cognition or mood state due to prolonged use of CBD (Allendorfer et al., 2019; Martin et al., 2019). Also, the link between CBD consumption and the possible effect on exercise-related recovery is primarily clinical and preclinical studies, mostly in participants with background pathology (McCartney et al., 2020). In this sense, more in-depth analysis is needed in the population of athletes to reach a conclusive statement.

Future Research and Limitations

As interest in the use of CBD in athlete recovery continues to grow, more research is required to better understand the physiological mechanism. The potential benefits, efficacy, and purported safety profile when consuming CBD prior to, during, and after training or competition should be explored. Future research in the field of sports science and medicine must focus on understanding the role of CBD in physiological mechanisms such as inflammatory cascade, neuroprotection, analgesic and anxiolytic pathways, muscle enhancement, and neuromechanical function.

New randomized placebo-controlled studies should consider the different etiologies of fatigue and damage, individualities and disciplines, and special needs and characteristics. Other potential research areas are, but are not limited to, optimal dosing depending on physical and physiological load; effectiveness regarding administration timing; chronic and acute effects; cumulative responses with other recovery strategies; differences in tolerance and effectiveness by sex, professional level, and fitness level; and other individual conditions and situational factors. Besides, more information is needed around the understanding of CBD inflammatory signaling as an essential factor in the recovery process. The effectiveness of CBD vs. conventional medications should be assessed.

This narrative review must be analyzed in light of some limitations. Though the main evidence about the use of CBD in sports was reviewed, this systematic review lacks explicit criteria for article selection and inclusion. In this sense, a systematic review could strengthen the actual conclusions and better present the preclinical and clinical evidence supporting the use of CBD in sports recovery. In this sense, a systematic review could better present settings of tests, study designs, demographics of participants, and main conclusions of the recent evidence.

Conclusion

Evidence supporting the potential use of CBD as an ergogenic aid to improve the efficacy and efficiency of recovery processes during exercise and sport-related fatigue seems promising. Still, there is not enough information to be conclusive. CBD appears to have some properties that could boost exercise recovery as an anti-inflammatory, neuroprotective, analgesic, anxiolytic, and pain reliever. Still, due to the lack of studies in elite athletes, there is a need for a better understanding of the effects of CBD as a physiological, physical, and cognitive recovery agent.

More evidence and higher-quality studies are required in populations related to sports science and exercise medicine to be able to give recommendations regarding the dose and frequency of consumption as well as the specific prescribing of CBD according to the intensity and duration of the effort, as well as the role of essential characteristics such as body composition, general health, and other situational factors in its effect. Also, considering the lack of regulations in CBD production and indiscriminate consumption, athletes must be cautioned due to the high risk of testing positive in the doping tests.

Cannabidiol seems to have anti-inflammatory, neuroprotective, analgesic, anxiolytic, and pain-relieving properties which can be potential mediators of recovery in athletes during regular training and competition. To confirm these effects, more scientific evidence in specific sport-related populations is necessary. There is a need for confirmatory analyses using randomized, placebo-controlled trials testing acute, and chronic effects of different dosing prescriptions. This study must consider some fundamental particularities of sports as a great variety of biological and situational conditions that promote fatigue, the characteristics of each discipline during training and competition, as well as the individual peculiarities of athletes, their tolerance and response to CBD intake, and the combined effect of CBD administration with other physical and nutritional aids.

Since training and competition leads to a structural and functional imbalance due to strenuous effort, CBD intake could potentially promote restoration of physical performance. The CBD physiological mechanisms of action, mixed with other recovery protocols, could help to reduce the accumulated fatigue evident over a tournament of consecutive efforts. The above may depend on pointing to multiple mechanisms to provoke global functional recovery in sports. Much evidence is needed to support this conclusion, but the proposed evidence looks promising.

Considering the relatively common use of both cannabis and CBD alone among athletes, there is a clear need to improve scientific understanding of the effects of CBD use on the fatigue, damage-related recovery, and performance of athletes. Greater scientific progress is needed, mostly on the execution of experimental trials, allowing a greater understanding of both critical positive and negative outcomes for the final benefit of the athletes in exercise-related recovery and performance. Also, the evidence resulted could give new clinical guidance to prescribe CBD during the recovery process of an athlete and other possible applications. The potential therapeutic benefits of CBD administration have been downplayed for years but, the actual scenario could facilitate the boost of the knowledge around this natural compound and its effects. Besides, from an administrative point of view, clearer and overarching policy for the use of cannabis in sports need to be considered and adopted.

Finally, athletes have to create an optimal internal environment to increase the function of endocannabinoids. In this sense, besides regular exercise, athletes must control weight, manage stress and competition-related anxiety, and minimize environmental exposure to contaminants and other toxic substances. These cannabimimetic practices would create the ideal environment for improving the endocannabinoid action in recovery.

Author Contributions

DR-V carried out the original idea conceptualization, literature search and systematization, writing the original draft, critically revising the manuscript, funding, and approving the final manuscript.

Conflict of Interest

The author declares that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest.

Publisher’s Note

All claims expressed in this article are solely those of the authors and do not necessarily represent those of their affiliated organizations, or those of the publisher, the editors and the reviewers. Any product that may be evaluated in this article, or claim that may be made by its manufacturer, is not guaranteed or endorsed by the publisher.

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