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

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, Δ9-tetrahydrocannabinol (Δ9-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.


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.

Molecular Targets
The distinctive intoxicating effects of Δ 9 -THC (as well as some of its therapeutic effects) involve the activation of CB 1 R (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 CB 1 R, 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 CB 2 R (the cannabinoid type 2 receptor) [12] and there is emerging evidence of CBD functioning as a partial agonist at this site [171]. CB 2 R 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 CB 1 R and CB 2 R, 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].
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 (t max ) was 4-5 h and the terminal half-life was~14-17 h. Although t max 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 t max (i.e.~2-3 h). Peak plasma concentrations (C max ) 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 interindividual 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, t max and C max 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 1). The USA Food and Drug Administration [30] recommend the following approach to interspecies dose conversion: 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 C max 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 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).

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 exerciseinduced 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].
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].
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 ironoverload [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 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 cotreatment has also been reported to attenuate CBDinduced analgesia, suggesting that the effect may be mediated, at least in part, by the TRPV 1 channel [40,41,51]. This mechanism is noteworthy as studies have  [66,140].
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 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, placebocontrolled trials of CBD in treating pain in clinical populations and athletes are warranted.

Exercise-Induced Gastrointestinal (GI) Damage
While strenuous exercise increases blood supply to the active skeletal muscles, cardiopulmonary system and skin-other organs and tissues, including the GI tract, experience reduced oxygen and nutrient delivery [180]. If exercise is prolonged (e.g. >40 min), this "GI ischemia", as well as the inflammation and oxidative stress that accompanies reperfusion, can compromise epithelial integrity [180]. Such effects may negatively influence exercise performance and post-exercise recovery due to GI distress (e.g. nausea, vomiting, abdominal angina, bloody diarrhoea) and impaired nutritional uptake [180].
Of course, it is important to recognise that evidence to support a therapeutic effect of CBD on GI damage in humans is currently lacking. In fact, two placebocontrolled, double-blinded clinical trials, one investigating the effect of CBD (10 mg·d −1 ; 56 days) on symptom severity in Crohn's disease (n = 20) [133] and the other examining the impact of a "CBD-rich botanical extract" (250 mg·day −1 [4.7% THC]; 56 d) on the likelihood of remission in ulcerative colitis (n = 60) [94], have so far been unable to demonstrate a protective effect of CBD (above placebo) on disease markers, including C-reactive protein, faecal calprotectin, and pro-inflammatory cytokines (e.g. IL-2, IL-6, TNF-α).
While CBD could potentially attenuate exercise-induced GI damage, it is important to note that other antiinflammatory agents, such as the NSAID, ibuprofen, have been reported to exacerbate exercise-induced GI damage and impair gut barrier function [181]. The precise mechanism(s) underpinning these effects have not been fully elucidated. However, NSAIDs have been suggested to augment GI ischemia by inhibiting the COX1 and COX2 enzymes and interfering with nitric oxide production [180]. Some in vitro research similarly suggests that CBD partially inhibits COX1 and COX2, although this effect has only been reported at supraphysiological concentrations (e.g. 50-500 μM CBD) [92]. Thus, the effect of CBD on exercise-induced GI damage warrants clarification.

Bone Health
While the beneficial effects of high-impact exercise on bone health are well established [38], other factors within the sporting context (e.g. traumatic injuries, low energy availability [117]) may cause or contribute to reduced bone health and the development of fractures in athletes.
A small number of preclinical studies have investigated the effects of CBD on bone structure and function [103,112,135]. While most have used animal models that are limited in their direct relevance to sport and/or exercise performance (e.g. periodontitis, systemic skeletal degeneration due to spinal cord injury) one investigation [103] did report that CBD improved the healing of femoral fractures in Sprague-Dawley rats. Specifically, chronic CBD treatment (i.e. 5 mg·kg -1 ·day -1 , i.p.) decreased callus size 4-weeks post-fracture and enhanced the biomechanical properties of the bone at 8-weeks (i.e. maximal force, work-to-failure on a 4-point bending test) [103]. While the mechanism(s) underlying this effect require clarification, CBD may act to inhibit expression of RANK and RANK-L (i.e. indicative of an effect to suppress osteoclastogenesis, and thus, bone resorption) and decrease the production of pro-inflammatory cytokines (e.g. IL-1β, TNF-α) at the site of injury [103,135]. Evidence that activation of CB 2 R induces bone matrix deposition has also recently emerged [150] alongside data suggesting that CBD may have partial agonist effects at this site [171]. These initial findings suggest that further research investigating the effect of CBD on acute skeletal injuries is worthwhile.  The "Treatment effects" described are in comparison to a placebo condition, unless otherwise stated
Taken together, these findings suggest that CBD has the potential to influence CV function. However, the implications of these effects in regard to exercise performance are unclear. Studies investigating the effect of CBD on exercise-induced CV responses are therefore required to clarify its utility within the sport and exercise context.

Thermoregulation
Heat loss mechanisms play a pivotal role in the maintenance of homeostasis during exercise; any treatment or condition that alters core body temperature (T C ), therefore has the potential to impact exercise performance [192]. The effect of CBD on T C has been investigated in rodents [65,82,83,85,96,118,166,182]. The most recently published study found that CBD (100 mg·mL −1 , 30 min vaporised; Wistar rats) reduced T C (−1.0°C) 60 and 90 min following inhalation in resting animals [96]. In contrast, Long et al. [118] reported a hyperthermic effect (+2.0°C) 30 min post-treatment (1 and 10 mg·kg −1 , i.p.; C57BL/6JArc mice) during a chronic-dosing experiment, although, this response was only observed intermittently during a 21-day protocol (e.g.~8% of total measurements). The fact that CBD affected T C in these experiments is difficult to explain, since although other cannabinoids (e.g. Δ 9 -THC, AEA) have demonstrated a capacity to moderate T C when administered exogenously (e.g. low doses of Δ 9 -THC may sometimes induce hyperthermia [168] and high doses cause hypothermia [65,82,83,85,96,118,166,182]), these effects occur via a CB 1 R-mediated mechanism [42,166,196]. In addition to this, no other studies appear to have detected changes in T C with CBD administration [65,82,83,85,166,182].
Overall, despite some inconsistencies, the available data suggest that CBD is unlikely to have a major influence on T C or thermoregulatory processes. In any case, it seems that with the exception of self-reported feelings of "coldness" [33,88], exogenous cannabinoids do not typically induce the same overt, significant effects on T C in humans [104,183] as are seen in rodents. Still, it should be acknowledged that the thermoregulatory response to heat stress (i.e. passive or metabolic), specifically, has not been studied.
That said, a mechanistic understanding of these effects of CBD on feeding behaviour remains to be established. Other cannabinoids with CB 1 R agonist effects (e.g. Δ 9 -THC, AEA, cannabinol) reliably induce hyperphagia when administered exogenously [58,197,198]; but CBD lacks such an effect. Ignatowska-Jankowska et al. [93] did report that the selective CB 2 R antagonist, AM630, prevented CBD-induced BM changes; however, CB 2 R has not generally been linked to feeding behaviour, and if CBD is indirectly increasing endocannabinoid tone (i.e. via AEA) [92], this might be expected to promote feeding behaviour (via indirect CB 1 R agonist effects) [197]. A role for GI side effects in affecting appetite therefore cannot be ruled out [107]. Further preclinical research appears to be required to clarify the mechanisms underlying these functional effects on feeding. Controlled trials are also needed to determine whether CBD influences appetite and dietary behaviour in humans, particularly during the pre-and post-exercise period, where nutrient provision is critical.

Illness and Infection
Some research suggests that athletes experience a decrease in immunity and are at increased risk of developing acute illnesses (particularly upper respiratory tract infections) during periods of heavy training and competition [184]. This phenomenon has been attributed to various factors such as increased psychological stress, poor sleep, long-haul travel, exposure to extreme environments (e.g. altitude), and low energy availability [184]. A recent review of online content identified a number of webpages claiming benefits of using CBD for the treatment of viral illnesses, including cold and flu [167]. However, research supporting such "protective effects" of CBD is extremely limited. In fact, the authors identified only two (in vitro) studies reporting antimicrobial effects [5,179] and two (in vitro) studies reporting anti-viral effects [119,122] (see Tagne et al. [167] and Nichols et al. [136] for reviews). In the former, CBD demonstrated anti-microbial activity against various strains of Staphylococcus aureus [5,179], as well as Staphylococcus pyogenes, Staphylococcus milleri, and Staphylococcus faecalis [179] at minimum concentrations of~3.2-15.9 μM; however, one study also found that these effects were virtually abolished when the original media (a nutrient broth agar) was replaced with one containing 5% blood (increasing the minimum concentration to~160 μM CBD) [179]. In the latter, CBD indicated anti-viral activity against the hepatitis C virus (EC 50 = 3.2 μM) and the Kaposi's sarcoma-associated herpesvirus (EC 50 = 2.1 μM), but not the hepatitis B virus [119,122]. While these findings hint at some promise, others caution that CBD could potentially weaken host defence against invading pathogens because of its tendency to modify the function of various immune cells (see also section "Exercise-Induced Muscle Damage-Muscle Function, Soreness, and Injury") [136,147]. Importantly, a systematic review of studies investigating the safety of CBD in individuals with intractable epilepsy found that upper respiratory tract infections were similarly infrequent in participants who received the active treatment (5-20 mg·kg −1 ·day −1 ) and placebo (approx. 10% of individuals) [107]. Further research to develop a better understanding of "if" and "how" CBD influences the development and progression of illness and infection in both athlete and non-athlete populations would be useful.

Sports Performance Anxiety (SPA)
High levels of pre-competition stress, or sports performance anxiety (SPA) [141], can be detrimental to athletic performance [43]. This impairment has been attributed to both the direct (i.e. anxiogenic) and indirect (e.g. decreased nutritional intake, increased energy expenditure, loss of sleep) effects of SPA [28]. While behaviour therapies (e.g. cognitive behavioural therapy) are the preferred treatment, a combination of pharmaceutical and psychological interventions may be indicated in some cases [141].
A number of (small) clinical trials have investigated the effect of CBD on subjective anxiety in healthy individuals [18,45,86,116,123,207,208] and in individuals with social anxiety disorder (SAD) [15,44,124] and high trait paranoia [90] under both standard (i.e. "low stress") [18,44,45,86,123,124] and "stress-inducing" (e.g. simulated public speaking) [15,90,116,207,208] conditions (Table 3). Overall, results suggest that CBD has little influence on anxiety under "low stress" conditions in healthy participants [18,86,123]. However, several studies have demonstrated anxiolytic effects of CBD (300-600 mg) under "stress-inducing" conditions in both healthy participants and those with SAD [15,44,116,124,207]. In fact, CBD (300 mg) had comparable efficacy to the anxiolytic 5-HT 1A agonist drug, ipsapirone (5 mg), during a simulated public speaking test in one study [207]. On the other hand, some other clinical investigations (involving similar "stress-inducing" stimuli) have found no effect of CBD [90,208] and Hundal et al. [90] observed a non-significant trend (p < 0.10) towards an anxiogenic effect with 600 mg CBD in a high trait paranoid group (n = 32). Inconsistencies could be due to inter-individual differences in baseline anxiety levels and the magnitude of the stress-response to the stressor imposed, small sample sizes, and differences in the dose and formulation of CBD provided. Indeed, Linares et al. [116] observed an inverted U-shaped dose-response relationship between acute CBD treatment and subjective anxiety, indicating that 300 mg (Hedges' g = 1.0) had a stronger anxiolytic effect than 150 mg (Hedges' g = 0.7) or 600 mg (Hedges' g = 0.6).
Taken together, it appears that moderate doses of CBD may be anxiolytic in stressful situations and in individuals with SAD. Thus, studies investigating the effect of CBD (in conjunction with behaviour therapies) on pre-competition anxiety, as well as nutritional intake, energy expenditure, symptom perception during exercise (e.g. ratings of perceived exertion), and sleep in athletes who are negatively impacted by SPA are warranted.

Sleep
The importance of adequate sleep in facilitating optimal athletic performance and recovery is increasingly recognised [121]. Yet, athletes often sleep less (e.g.~6.5-6.7 h·night −1 ) and experience poorer quality sleep than nonathletes [79,109,152]. Factors that contribute to poor sleep among athletes include evening competitions and training sessions, pre-competition anxiety, use of caffeine, and long-haul travel (e.g. jet lag, travel fatigue) [121].
Several studies have investigated the effect of CBD on sleep in humans [26,32,115,157]. The first placebocontrolled, double-blinded (single-dose) crossover trial [26] found that 160 mg CBD (but not 40 or 80 mg) increased self-reported sleep duration in individuals with insomnia (n = 15); although time to sleep onset, number of sleep interruptions, and likelihood of experiencing "good sleep" were unchanged. Two case studies also indicated the benefits of CBD [32,157]. Specifically, Chagas et al. [32] observed a reduction in symptoms of rapid eye movement sleep-behaviour disorder in four individuals with Parkinson's disease (75-300 mg·day −1 ; 42 day) and Shannon et al. [157] found that CBD (~25 mg·day −1 ) improved subjective sleep quality in a young girl with post-traumatic stress disorder (PTSD). Of course, these studies [26,32,157] are limited in that they rely on subjective measures of sleep and involve small sample sizes; the improvements observed could also be due to CBD attenuating other sleep-impairing comorbid conditions (e.g. anxiety, PTSD). Indeed, a recent placebo-controlled, double-blinded (single-dose) crossover trial [115] found no effect of CBD (300 mg) on sleep architecture measured via polysomnography in healthy adults (n = 27).
While CBD seems unlikely to directly influence sleep in healthy humans [115] (and may be "sleep-promoting" in those with certain comorbid conditions) [26,32,157], a small number of rodent studies suggest that the cannabinoid could actually be "wake-inducing" [128,132,204]. One placebo-controlled, double-blinded (single-dose) crossover trial of healthy individuals (n = 8) [137] also found that low-dose CBD (15 mg) counteracted some of the sedative effects of co-administered Δ 9 -THC (15 mg), i.e. increasing overnight wakefulness; although, this effect could be due to CBD acting as a NAM of CB 1 R, thereby attenuating Δ 9 -THCs effects on that receptor [92]. Differences in the doses of CBD administered might partly explain this inconsistency. Indeed, Monti [128] observed a biphasic effect of CBD on sleep in Wistar rats, such that a lower dose decreased, and a higher dose increased (20 vs. 40 mg·kg −1 , i.p.), slow-wave sleep latency. However, inter-species differences are also a consideration as nocturnal animals appear to exhibit different circadian patterns of endocannabinoid signaling compared to humans [84,131]. Collectively, the current evidence on CBD and sleep endorses the need for further research in clinical populations and athletes.

Cognitive and Psychomotor Function
A small number of clinical trials have investigated the effects of CBD on cognitive and psychomotor function in healthy individuals (Table 4). Overall, results suggest a minimal influence of CBD on cognitive or psychomotor function. While one early investigation [98] reported that CBD (15 or 60 mg) caused participants to under-/over-estimate the duration of a 60-s interval on several occasions throughout a repetitive testing protocol (i.e. as is indicative of impaired concentration), the magnitude of error was small (e.g. <5 s; particularly, in comparison to that observed with Δ 9 -THC, e.g.~10-25 s [98]) and the effect was inconsistent, suggesting it may be an artefact of the between-subject design and small sample size. A more recent investigation [86] observed an improvement in emotion recognition with CBD (16 mg vaporised); however, this "ability" may have limited relevance to the sporting context. More applicable, perhaps, is Dalton et al. [49] finding no effect of CBD (150 μg·kg −1 vaporised) on balance or coordination (a product of both cognitive and motor function). A more recent investigation likewise found no effect of oral or vaporised CBD (100 mg) on cognitive performance between 30 min and 8 h posttreatment [160] (Table 4). Thus, while only a narrow range of doses and relatively few discrete cognitive functions have been studied, the available data suggest that CBD is unlikely to impact cognitive or psychomotor function on healthy individuals.

CBD "Nutraceutical" Products
Over-the-counter CBD-containing "nutraceuticals" are now readily available in many countries and of increasing WSD within-subject design The "Treatment effects" described are in comparison to a placebo condition, unless otherwise stated a Time estimation task: participants were asked to produce a 60 s interval 10 times. The first 5 estimations were without feedback and the remaining 5 were with feedback. This task was repeated 45, 95. and 180 min post-treatment interest to the community [108]. However, it is important to be aware that these products are often limited in that they typically contain low levels of CBD (e.g.~10-50 mg·mL −1 ), [20] making it difficult to achieve the higher doses often used in the studies described in this review. Additionally, over-the-counter CBD nutraceuticals are not always manufactured to the same pharmaceutical standards as regulated, prescription CBD products (e.g. Epidiolex®). Indeed, a recent study [20] reported that onlỹ 31% of CBD extracts sold online (n = 84) were "labelled accurately" (i.e. a measured CBD content within 10% of the labelled value); nearly half underestimated, and a quarter overestimated, their CBD content-approximately one-fifth of samples also contained detectable levels of Δ 9 -THC. A similar investigation [148] of nine CBD "e-liquids" (used for vaporising) found that two contained Δ 9 -THC, four contained 5-fluoro MDMB-PINACA (a potent synthetic cannabinoid receptor agonist with powerful psychoactive effects), and one contained dextromethorphan. Thus, individuals using these products are at risk of over-/ under-dosing, adverse health effects and/or possibly, recording a positive drug test result. This suggests that until such time as better manufacturing standards are imposed, athletes in competition might wish to avoid using nonregulated CBD-containing nutraceuticals, or, at least carefully investigating their quality control and provenance before using them.

Conversion of CBD to Δ 9 -THC
In vitro studies have shown that CBD can undergo conversion to Δ 9 -THC with prolonged exposure to simulated gastric fluid [126,189]. However, this effect has not been observed in vivo. When investigating the phenomenon in minipigs (30 mg CBD·kg −1 ·day −1 , oral 5 days), which, like humans, have omnivorous diets and other GI similarities (e.g. pH, transit time, drug absorption), Wray et al. [202] found no detectable (i.e. <0.5 ng·mL −1 ) Δ 9 -THC or 11-OH-THC in any plasma or GI tract samples collected. Consroe et al. [37] also found no detectable Δ 9 -THC (i.e. <0.5 ng·mL −1 ) in human plasma following chronic highdose CBD treatment (700 mg·day −1 ; 30 days). These data suggest that pure CBD is unlikely to produce a positive drug test result (i.e. indicated by a urinary THC-COOH level > 150 ng·mL −1 [200]) or any intoxicating (ergolytic) effects due to conversion to Δ 9 -THC. To date, however, no studies have directly investigated whether CBD can elicit a positive drug test result in athletes.

Conclusions
CBD has been reported to exert a number of physiological, biochemical, and psychological effects, that have the potential to benefit athletes. For instance, there is preliminary supportive evidence for anti-inflammatory, neuroprotective, analgesic, and anxiolytic actions of CBD and the possibility it may protect against GI damage associated with inflammation and promote the healing of traumatic skeletal injuries. However, it is important to recognise that these findings are very preliminary, at times inconsistent, and largely derived from preclinical studies. Such studies are limited in their generalisability to athletes (and humans in general), and often administer high doses of CBD that may be difficult to replicate in humans. The central observation is that studies directly investigating CBD and sports performance are lacking, and until these are conducted, we can only speculate in regard to its effects. Nonetheless, this review suggests that rigorous, controlled investigations clarifying the utility of CBD in the sporting context are clearly warranted.