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Nutritional Supplements for the Treatment and Prevention of Sports-Related Concussion—Evidence Still Lacking

Trojian, Thomas H. MD, MMB, FACSM1; Wang, David H. MD, MS2; Leddy, John J. MD, FACSM, FACP3

doi: 10.1249/JSR.0000000000000387
Nutrition and Ergogenic Aids: Section Article
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Concussions are common neurologic events that affect many athletes. Very little has been studied on the treatment of concussions with supplements and medications. The U.S. Food and Drug Administration (FDA) reminds us that no supplement has been proven to treat concussions. Many animal studies show that supplements have potential for improving the effects of a brain injury but none have been shown to be of consistent benefit in human studies. Animal studies on severe traumatic brain injury (TBI) may not therefore be applicable transfer to sports-related concussions (SRC).

Of the many supplements reviewed in this article, omega-3 fatty acids (Ω-3 FA) have potential for SRC treatment but in the one human trial those taking higher dosages preinjury had more concussions. In animal studies, postinjury administration was as effective as pretreatment. N-acetyl-cysteine has demonstrated a positive short-term effect on blast injuries in soldiers if administered within 24 h, but there are no studies in SRC. Caffeine, conversely, may be detrimental if taken after SRC. Lower serum levels of vitamins D, C, or E preinjury have worse outcomes in animal studies. Preinjury correction of deficiencies may be of benefit. Current human trials for nicotinamide ribose, melatonin, and branched chain amino acids (BCAA) may soon provide more evidence for the use of these supplements to reduce the impact of SRC in athletes.

1Division of Sports Medicine, Department of Family, Community & Preventative Medicine, Drexel University, College of Medicine, Philadelphia, PA 19127; 2Connecticut Children’s Medical Center, Elite Sports Medicine, Farmington, CT; and 3UBMD Department of Orthopaedics and Sports Medicine, SUNY Buffalo Buffalo, NY

Address for correspondence: Thomas H. Trojian, MD, MMB, FACSM, Division of Sports Medicine, Department of Family, Community & Preventative Medicine, Drexel University, College of Medicine, 10 Shurs Lane, Suite 301, Philadelphia, PA 19127; E-mail: Thomas.Trojian@drexelmed.edu.

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Introduction

A concussion is an injury that disrupts the normal function of the brain that can be caused by a blow to the head or body resulting in a rapid acceleration and deceleration of the calvarium (38). Concussions are common in collision sports resulting in variable recovery times in athletes. The cerebral physiology is adversely affected causing significant neurometabolic derangements (13). After a head injury, there is a posttraumatic depolarization and potassium efflux from cells that trigger the release of excitatory amino acid (EAA)-like glutamine, which in turn activate N-methyl-D-aspartate (NMDA) receptors and form a pore through which calcium enters the neuron (111). A large influx of calcium into the cell triggers the lysis of EAA and the formation of reactive oxygen species (ROS) (111). The negative effects of ROS overproduction and activation of inducible nitric oxide synthase is seen in repeat mild traumatic brain injury (mTBI) (105).

The release of cytokines and EAA are normally contained to the area of inflammation associated with the injury (73). Secondary injury to the brain occurs within minutes, days, but can evolve over weeks after the initial insult, which is the result of cascades of these metabolic, cellular, and molecular events (77). These events occur alongside the alterations of endogenous neurochemical, inflammatory, and neuroinflammatory mechanisms. All of these alterations are linked directly or indirectly to neuroinflammation (73). Such mechanisms ultimately lead to brain cell death or rescue, plasticity, tissue damage, and atrophy, depending on the severity of the injury (20,25). Altering these changes in the brain theoretically may lead to faster recovery and less severe damage (13,20). Unfortunately, to date, there have not been any universally accepted treatments for concussion, besides cognitive and physical rest, with recent data questioning the need for strict physical rest after concussion (56).

As posted on the Food and Drug Administration (FDA) web site, “There is simply no scientific evidence to support the use of any dietary supplement for the prevention of concussions or the reduction of postconcussion symptoms that would allow athletes to return to play sooner” (1). Most of the nutritional treatments for concussion are derived from preclinical and animal model studies. So, most of our discussion of supplements should be considered theoretical. We feel that vitamins, supplements, and minerals without preclinical data, clinical evidence, or are uncommon without strong evidence for usage should not be discussed in this article. As well, we do not speculate if combining supplements will have an enhancing or cancelling effect. Remember, progesterone (PROG) was considered promising for concussion treatment (87), but in phase III trials, it failed (65), so caution should be used.

Some researchers have suggested that individual supplements do not treat a complex problem and that further research should be based on two main therapeutic targets related to oxidative stress cell damage:

  1. NADPH oxidase inhibition: such as with vitamin C and vitamin E.
  2. Functional stabilization of the mitochondrial electron transport chain complexes, such as with melatonin.

In studies evaluating the effectiveness of supplements, it is important to consider the measurement used to define improvement. This allows for determining clinical validity of the study. For prevention treatments, a dose-effect relationship should be seen for a well-defined outcome, such as reduction in diagnosed concussions. For treatment, a validated tool like the Rivermead Post-Concussion Symptom Scale (PCSS) (51), divided into somatic symptoms, neurobehavioral symptoms, and “cognitive” symptoms (43,54,80), but not one total score (29), could be a useful measure. Serum biomarkers for the diagnosis and prognosis of concussions have limitations in usefulness. Serum markers like ubiquitin carboxyl terminal hydrolase L1 (UCH-L1) and S100β had no additional clinical usefulness in diagnosing sports-related concussions (SRC) in a recent study with positive likelihood ratios of 1.0 but glial fibrillary acidic protein (GFAP) had a strong likelihood ratio of 8.7 for a concussion (57). S100β usefulness seems to be more in the area of mTBI to severe TBI (108,109). A proteolytic fragment of alpha-II spectrin (SNTF) was found to be elevated in serum after mild TBI in patients (100) and to have prognostic features for poor clinical outcome (99). This marker has been associated with diffuse axonal injury (49).

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Omega-3 Fatty Acids

Much has been touted about the usefulness of eicosapentaenoic acid (EPA) (C20:5) and docosahexaenoic acid (DHA) (C22:6) for the treatment of concussions (15,111). The potential connection between DHA and treatment of concussions is well founded with sound basic science (42). DHA is essential for brain development and normal brain function (11,15). DHA constitutes up to 97% of the omega-3 fatty acid (Ω-3 FA) in the brain (15). Ω-3 FA supplementation reduces synthesis of inflammatory cytokines, such as interleukin-1 and tumor necrosis factor (11,42), and reduces ROS production by leukocytes (11,42). Both of the aforementioned effects are potentially important in the recovery from a concussion. EPA and DHA are precursors for resolvins (15). DHA also serves as the precursor for synthesis of protectins (52). Both resolvins and protectins bring about a programmed resolution of the inflammatory process (52), which may aid in the limitation of damage from concussions.

The potential neuroprotective benefits of omega-3s are evident from animal studies demonstrating that supplementation before or after TBI protects the brain by limiting structural damage to the axon and neuronal apoptosis (111). Multiple animal studies show benefit with postconcussion (10,117,118) and pretreatment dosing of fish oil (69). A 10 mg·kg−1 of EPA and DHA per day in a 2:1 ratio or 10 mg·kg−1·d−1 of DHA alone seem to be sufficient if started immediately after a concussion (within 24 h) (15,111).

A recent study evaluated the effect of DHA on head trauma in American football players. Athletes given placebo, 2, 4, and 6 g·d−1 of DHA had neurofilament light (NFL) measured across the season weekly (74). The authors claimed that subjects taking placebo were found to have elevated serum NFL levels in the last two time measures, demonstrating a benefit for weekly DHA supplementation. This study is limited because the analysis was limited to starters, those without known concussion during the season, and to those taking 80% of tablets. Furthermore, there was no linear benefit of the larger 6 and 4 g·d−1 doses, which had higher serum NFL than the 2-g·d−1 dose, and there was no individual independent weekly screening for concussions (74). This is important because it is known that NFL levels can increase more than 400% in an individual after a boxing match that can last for more than 2 wk (76). With such a small subgroup (11 subjects) analysis, a person in the placebo group could have had a head injury in the last 2 wk and elevation in NFL and skewed the data. This is especially significant in the assessment of the literature because there was no dose-effect curve (improvement as dosage increased) and the need to greatly subgroup the analysis to only 33 players versus the 115 consented for the study (74).

When looking at these results, it is important to note that NFL is a surrogate endpoint, and the study was not an intention-to-treat analysis. The researchers dropped from analysis those not taking 80% of tablets (which were mostly those in the 4- and 6-g group) and dropped those with known concussions during the season (which occurred in only the 4- and 6-g group) (74), with more concussions in those on the higher the dose. The researchers came up with a recommendation of at least 2 g·d−1 for American football players (74). One needs to note that those taking 4 and 6 g were the only groups to have a recorded concussion, with the 6-g group having five concussions in 30 subjects versus none in the placebo and none in the 2 g group of 52 consented subjects. Further work is therefore needed to see if more DHA makes you more likely to become concussed while playing football.

If we are uncertain about the benefits of fish oil in humans, one might question using fish oil or DHA in humans to prevent or treat concussion. The main side effects of fish oil include belching, bad breath, “fishy burp,” heartburn, nausea, and loose stools (111). There is more of a theoretical than practical risk of bleeding in athletes, with some cases of bleeding cited with fish oil use (111). The animal data do not show added benefit from preloading DHA versus initiating treatment within 24 h (15,111). Therefore, if one chooses to use DHA despite the lack of data, we would suggest it be used postinjury, 10 mg·kg−1·d−1 or 2 g·d−1.

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Nicotinamide Ribose

Nicotinamide, or vitamin B3, is a precursor of nicotinamide adenine dinucleotide (NAD+) and is involved in a multitude of intracellular and intercellular processes, which regulate some of the cell's metabolic, stress, and immune responses to physiological or pathological signals (85). Nicotinamide riboside is a form of vitamin B3 found in dairy milk, yeast, and beer (22). Nicotinamide riboside may be the only vitamin precursor that supports neuronal NAD+ synthesis (19). Nicotinamide riboside effects of raising tissue NAD concentrations in rodents may be important in recovery from brain injury (22). Sterile alpha and TIR motif-containing 1 (SARM1) protein is an essential mediator of axon degeneration (34). Axon degeneration is an intrinsic self-destruction program that underlies axon loss during injury and disease (33). Increased nicotinamide riboside reduces the damage from SARM1 in rats (33).

A human trial of nicotinamide riboside supplementation in American football athletes is being conducted (NCT02721537). It is using Functional MRI to evaluate if NAD+ changes in a double blinded placebo controlled trial. This supplement has potential and further studies may lead to better understanding. We are not recommending using this supplement but promising animal studies and current human trials are why we mention it in this article.

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Magnesium and Riboflavin (Vitamin B2)

Magnesium (Mg) is an essential mineral nutrient that plays a role in the stability of all polyphosphate compounds in cells. It binds to ATP to make ATP biologically active and is therefore essential for mitochondrial membrane stability and coupling of oxidative phosphorylation (86). When a concussion occurs, there is a transient neurologic dysfunction that results from a biomechanical force (13). Mg levels decrease intracellularly, which in turn alters neurochemical balance due to the lack of maintenance of cellular membrane potentials (13). The low Mg levels effectively unblock NMDA receptor channels, allowing for greater influx of Ca2+ causing deleterious intracellular damage (13). These reactions have toxic effects on the brain's chemical balance and further perpetuate concussion symptomology while impairing the overall recovery process.

Phosphorus magnetic resonance spectroscopy (31P-MRS) studies have shown abnormal energy metabolism in the brains of patients with different types of migraine and cluster headaches (70), suggesting that imbalance between mitochondrial ATP production and energy demand may play a central role in the pathogenesis of these disorders. Low cytosolic free Mg has been found in the brains of patients with migraine with and without aura during attacks (82) and between attacks in young patients with migraine with aura (61). A mitochondrial defect may reduce the threshold for migraine attacks by both increasing neuronal excitability and predisposing the brain during a migraine attack to a hyper-responsiveness to triggering stimuli. Lodi et al. (60) found reduced interictal cytosolic free Mg concentration in the occipital lobes of patients with different types of migraine and cluster headaches matched by a decreased amount of energy release during ATP hydrolysis, both variables being more abnormal in migraine patients with a more severe clinical phenotype. Thus, low free Mg may contribute to the energy deficit observed in migraine headache patients.

Studies suggest that Mg can diminish the likelihood of starting an immunoexcitotoxic reaction, especially in individuals with hypomagnesaemia (73). Studies in both animals and humans have shown that Mg depletion is significant after TBI and remains low for up to 4 d, which causes cells to be less capable of providing sufficient energy for repair and restoration, inducing apoptosis (13).

Currently, studies do not support the use of Mg salts in individuals with severe TBI because it does not influence mortality outcomes (4). Mg sulfate, however, has shown improvement in both the Glasgow Outcome Scale and Glasgow Coma Scale scores and shows promise as a therapeutic agent in this aspect (58). Its role in recovery is important in both glycolytic and oxidative generation of ATP, which becomes impaired when Mg levels are low (13). Therefore, this could impact the recovery time period in an individual with a concussion and improve motor performance.

Riboflavin (vitamin B2) is a vitamin found in food. Like Mg, it may have relevance to the altered brain energy metabolism that is believed to exist in patients who suffer from migraine headaches since riboflavin is a major co-factor in oxidative metabolism (23). For example, an animal study showed that riboflavin administration significantly improved behavioral outcome and reduced lesion volume, edema formation, and the expression of GFAP after traumatic frontal cortex contusion injury (101). These findings suggest that riboflavin may have therapeutic potential for the treatment of human TBI (45). The combination of Mg chloride and riboflavin may be even more powerful. In another animal study, the combination of the two significantly improved functional recovery to a greater extent than the individual treatments when administered shortly after frontal cortical contusion injury in a rat model (12). These findings suggest that administration of Mg plus riboflavin may provide better therapeutic action than each substance alone.

With respect to clinical use in concussion, Mg and riboflavin may reduce the frequency or the severity of posttraumatic migraine headaches, which are not uncommon after concussion (53,106). These substances may be useful in other headache types as well. In an uncontrolled study of episodic tension-type headache at a pediatric headache clinic, Mg pidolate (2.25 g) given twice per day for 3 months improved symptoms so that analgesic use decreased significantly (36). In a randomized double-blind placebo controlled trial of a proprietary supplement containing Mg, riboflavin, and Q10, there was no affect on headache frequency but the severity of symptoms was significantly reduced compared with placebo in patients with migraine attacks (31). A randomized double-blind placebo-controlled trial of a compound providing a daily dose of riboflavin, 400 mg; Mg, 300 mg; and feverfew, 100 mg versus a “placebo” containing 25 mg riboflavin showed a significant reduction in the frequency of migraines headaches and symptoms when compared with baseline in both groups, suggesting that riboflavin may have been the effective agent (66). Thus, Mg and riboflavin supplements may have roles in the treatment of postconcussion headaches, particularly migraine headaches, but properly designed and powered clinical efficacy trials in humans after concussion have not been performed.

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Curcumin

Curcumin is a flavonoid compound that is the principal curcuminoid of the Indian spice turmeric. It is a member of the ginger family. Commonly known because it provides the yellow pigment seen in many curries, Curcumin may have significant neuroprotection because it acts on multiple deleterious posttraumatic molecular cascades. Flavonoids may exert a multiplicity of neuroprotective actions within the brain: protection of neurons against injury induced by neurotoxins (68); suppression of neuroinflammation (20,120); and potential to promote memory, learning, and cognitive function (78). Flavonoids are believed to interact with critical protein and lipid kinase signaling cascades in the brain to inhibit apoptosis and promote neuronal survival and synaptic plasticity (20). Animal studies show that Curcumin is a potent Nrf2 inducer and effective as a neuroprotectant in TBI (42,90). Polyphenolic derivatives of curcumin also have been shown to protect the rat brain against the effects of experimental TBI by decreasing oxidative stress (42,90) mitigating posttraumatic reactive astrogliosis and preventing upregulation of the water channel aquaporin 4 (6).

Curcumin has the potential to regulate molecules involved in energy homeostasis after TBI (95). Results suggest that curcumin administration postinjury may improve patient outcome by reducing acute activation of microglia/macrophages and neuronal apoptosis in TBI (120). Both pretraumatic and posttraumatic curcumin administration resulted inhibition of inhibited the proinflammatory molecules interleukin 1β and nuclear factor kappa B (NFκB) (78). Prophylactic administration of curcumin exerted greater effects than posttraumatic treatment and the major problem is that the therapeutic window for significant neuroprotection was less than 1 h post-TBI (90,95). Because the work is currently preclinical in animal studies, there is no recommended dose.

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N-Acetyl Cysteine

N-acetyl cysteine (NAC) is acetyl derivative of the amino acid cysteine. It is widely available as an over-the-counter nutritional supplement with antioxidant properties (26). NAC is considered a well-tolerated and safe medication that has been used all across the world in a variety of medical conditions for several decades, including its use in acetaminophen overdose (26).

An animal study on the effects of NAC revealed significant behavioral recovery after TBI (27). The benefit was seen in both mice and rats when NAC was administered within 60 min of injury. Other animal TBI studies have shown benefit of NAC alone or in combination with minocycline or selenium (28,40,46,93). In humans, a double-blind placebo-controlled clinical trial in 80 soldiers who sustained a mild traumatic brain blast injury showed that more blast-injured soldiers were symptom free at day 7 compared with placebo (46). Dosing was a 4-g loading dose, 4 g daily (in two divided doses of 2 g morning and night) for 4 d, then 3 g in two divided doses of 1.5 g morning and night (46), best initiated within 24 h (46).

NAC is one of the only supplements to have clinical trials, though it is blast injuries not SRC. The data are promising. NAC is likely safe for most adults when used as a supplement for concussion but it can cause nausea, vomiting, and diarrhea or constipation (16). It has a major interaction with nitroglycerin causing vasodilation, which is important to know as a sports medicine physician (16).

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Resveratrol

Resveratrol is a naturally occurring phytoalexin and stilbenoid compound found in multiple dietary sources, including red wine, grapes, and peanuts (62). Resveratrol has antioxidant properties and has been touted for its cardioprotective effects. After a significant neurologic insult, there is an increase in the presence of superoxide radicals, which can induce lipid peroxidation of arachidonic acid (AA), a significant component of neuronal cell membranes (42). The breakdown of AA leads to neurotoxic aldehydes that inhibit the functions of the cellular proteins leading to a secondary neurologic insult (42). Resveratrol possesses multiple phenolic hydroxyl groups that can donate electrons to neutralize free radicals (42). Resveratrol is a scavenger of the lipid peroxyl radicals created from lipid peroxidation after neurologic injury (68).

Resveratrol crosses the blood-brain barrier and has been studied in the animal model following neurologic injury. Studies of resveratrol in rodents after experimental TBI demonstrate reduced neuronal loss as well as improved behavioral measures (102). Treatment with resveratrol (100 mg·kg−1 single dose) immediately after TBI reduced oxidative stress and lesion volume in rats (7). Research continues as the potential benefits of resveratrol not only include its antioxidant properties but also the ability to increase cerebral blood flow (115,116) and inhibition of the proinflammatory molecule NFκB (62) in healthy individuals. To date, there have not been any published human trials with resveratrol for mTBI nor concussions.

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Vitamins E and C

Lipid peroxidation inhibitors have been reported to be effective neuroprotectants in TBI models (42). Vitamin E is a potent, lipid-soluble, lipid peroxidation inhibitor that is present in high concentrations in the mammalian brain (78). Vitamin C, ascorbic acid, as a free radical scavenger, also transforms vitamin E to its active form. While vitamin E has high lipid solubility and low toxicity, it takes a considerable amount of time to reach effective levels in the CNS (97). At high dosages, vitamin E can cause hemorrhage. Vitamin C has little danger in high dosages (92).

Rats treated with vitamin E postconcussion had decreased functional neurologic deficits and microscopic brain damage (24), reduced lipid peroxidation (oxidative stress), and reduced amyloid accumulation (6). When vitamin C is supplemented with vitamin E, there is a significantly less brain injury due to oxidative stress than supplementation with either vitamin E or vitamin C alone (47). Vitamins C and E supplementation has been studied in humans after severe TBI (84). Subjects with very low Glasgow Coma Scale scores (≤8) and with radiographic evidence of diffuse axonal injury had decreased mortality and increased Glasgow Outcome Scores if treated with vitamin E and decreased edema and lesion size if treated with vitamin C (84). Treatment with both was better than each treatment alone.

While basic science and animal data point to a beneficial effect of maximizing vitamin E and vitamin C before concussions, there have been no human concussion trials on the efficacy of vitamin E and/or vitamin C.

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Vitamin D

Vitamin D is important for many functions in the body. Cells in the central nervous system have vitamin D receptors that modulate gene transcription responsible for neuronal proliferation and maintenance of calcium homeostasis (39). Vitamin D deficiency may increase inflammatory damage and behavioral impairment after experimental head injury (78). Vitamin D deficiency has been reported in up to 20% to 30% of the athletes (9,30). There is a seasonality to vitamin D deficiency, with a higher incidence in the winter (9,67), indoor athletes are at higher risk than outdoor athletes, and the risk increases from the southern United States to the northern United States (67).

The combination of PROG and vitamin D in one study of patients with severe TBI resulted in significantly improved Glasgow Outcome Scale scores, that is, a better recovery rate (55). Vitamin D monotherapy independently reduced inflammation and neuronal injury after TBI, with a more robust effect observed in combination with PROG (55). The reason for the interaction of vitamin D and PROG has not been determined but may represent a combination of reductions in astrocyte activation and NFκB phosphorylation (104).

Though vitamin D deficiency appears to be detrimental for concussions, and vitamin D may be beneficial for other athletic related reasons (110), studies are needed on the potential benefit for supplementing vitamin D after SRC. When considering replacing vitamin D in athletes with low levels (minimal level of 32 ng·mL−1) (110,113), it is often done at 50,000 IU·wk−1 (110,113). One study looking at high dose replacement found that 70,000 IU·wk−1 (10,000 IU·d−1) may be detrimental (75) causing increased side effects and overdose symptoms. Five thousand IU per day appears to be a tolerated replacement dosage.

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Melatonin

Melatonin is a hormone secreted by the pineal gland in the brain that helps to regulate sleep and wake cycles (119). Melatonin crosses the blood-brain barrier and has been shown to be a versatile hormone having antioxidative, antiapoptotic, neuroprotective, and anti-inflammatory properties (72). Animal studies show that melatonin has a neuroprotective role in the injured part of the brain after mTBI to severe TBI (72).

Sleep-wake disturbances are common after TBI (79). While not all of the reasons are clear, reduced evening melatonin production may indicate disruption to circadian regulation of melatonin synthesis after brain injury. In patients with severe TBI, melatonin production was attenuated overnight and the timing of melatonin secretion was delayed (37). Patients with mTBI to severe TBI report greater sleep disturbance than controls, show decreased sleep efficiency, increased wake after sleep onset, and have significantly lower levels of evening melatonin production associated with less rapid eye movement (REM) sleep (79,96). Recent studies suggest that sleep difficulty is significantly predictive of prolonged recovery from concussion (107). The lack of normal sleep could be problematic for effective concussion healing and recovery (17). In a recent study of both athletes and nonathletes with persistent postconcussive symptoms (PPCS, greater than 6 wk) who reported sleep problems on the Insomnia Severity Index (ISI) and concussion symptoms on the PCSS, sleep disturbance significantly contributed to the severity of postconcussive symptoms and length of recovery. Interestingly, the effect was less pronounced in athletes (44).

Melatonin has been successfully used to alleviate jet lag symptoms of travelers, and there is some evidence that it helps shift workers adjust to nocturnal regimens (8), but the neuroprotective effects of melatonin seen in the animal models have not been studied in humans. Melatonin may be effective in treating several primary headache disorders, particularly cluster headache and migraine (32). A recent randomized placebo-controlled trial of melatonin 3 mg (immediate release taken at bedtime) in adults showed that it significantly reduced headache frequency compared with placebo and was superior to amitriptyline in the percentage of patients with a greater than 50% reduction in migraine frequency (35). Melatonin also was better tolerated than amitriptyline. A recent systematic review concluded that the evidence for the effectiveness of melatonin for postpediatric TBI sleep impairment appears promising (50). The timing and dose of melatonin vary depending on the patient and the situation (e.g., treating jet lag versus helping sleep onset in the elderly) (5). For the delayed sleep phase that appears to be the problem in concussion and TBI patients, a dose of 0.5 mg to 5 mg initially to advance the internal clock (usually late afternoon/early evening, such as 8:00 PM (112)) and, after realignment, a maintenance dose just before normal bedtime is reasonable (5). A randomized, double-blind, placebo-controlled superiority trial of melatonin in concussed children who report subsequent sleep issues is ongoing with a planned end date in 2019 (Play Game Trial) (14).

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Caffeine

Caffeine is a well-known stimulant with a primary inhibitory activity at the adenosine 1 (A1) and A2A receptors (63). This inhibition might interfere with the neuroprotective effect of adenosine in ischemic-hypoxic conditions (2). A1 receptor mediates the suppression of glutamate release and inhibition of excessive inflammatory cytokine production (59).Caffeine would inhibit the potential benefit of adenosine in concussions.

Most studies looking at the effects of caffeine are in the severe TBI model in rats (59,64,88,114). Severe human TBI studies have found that elevated cerebral spinal fluid caffeine levels at the time of injury showed an outcome benefit (88). Other animal studies have shown that chronic but not acute ingestion of caffeine is beneficial in severe TBI (59). Chronic caffeine treatment resulted in increased A1 receptor mRNA expression (59). This increase in adenosine receptors is a theoretical reason for a protective effect of chronic caffeine ingestion.

There are studies showing adverse outcomes with acute caffeine administration in mild TBI (2,59). Caffeine stimulates IP-3 receptor-mediated intracellular calcium release and activates adenylyl cyclase, which catalyzes ATP into cAMP (63). Clear differences between concussion and severe TBI measurement of cAMP concentration in CSF might have diagnostic value in evaluation of the severity of cerebral injury in the acute phase (71). This may explain the difference of the effectiveness of caffeine among severe and mild TBI.

Acute caffeine ingestion may therefore affect recovery from a concussion. Randomized studies in humans are needed to determine if we should recommend avoidance after injury. Caffeine usage is so common in athletes that future studies should be priority. Neurocognitive testing is common in the evaluation of readiness for return to play. Stimulant ingestion 30 min before testing resulted in improved memory, visual processing speed, and reaction time (81). This may affect return to play decisions. We currently cannot recommend caffeine postinjury and there is theoretical reason to be concerned with adverse outcomes when caffeine is taken within hours of injury.

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Branched Chain Amino Acids

Branched chain amino acids (BCAA) consist of the essential amino acids leucine, isoleucine, and valine. The BCAA are used in muscle protein synthesis but also readily cross the blood brain barrier and are an integral part of neurotransmitter synthesis (94). BCAA are needed to produce the neurotransmitters glutamate and gamma aminobutyric acid (GABA) (94). Glutamate stimulates neurons while GABA inhibits them. The best sources of the BCAA are diary and meats, but they also can be found in beans, nuts, corn, and certain grains.

In human TBI, levels have been shown to be decreased compared with controls (48). This suggests that the neurometabolic cascade associated with a brain injury influences BCAA levels (48). Human severe TBI studies have been performed with the supplementation of BCAA after the injury. In these studies, patients that had suffered significant brain injury demonstrated cognitive benefits from BCAA supplementation. In one study after severe TBI, BCAA-supplemented patients scored better on the Disability Rating Scale compared to the placebo group. These benefits were measured on day 15 after the injury as well as at discharge (3).

BCAA use in concussion treatment remains intriguing given the benefits noted with more severe brain injuries but there are no studies of the efficacy of BCAA supplementation after a more mild injury, such as a concussion or its use for the prevention of concussion (94).

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Creatine

Creatine is an amino acid naturally synthesized in the liver, kidneys, and pancreas from the amino acids glycine, arginine, and methionine (41). Creatine also can be obtained from protein rich foods, such as meat, fish, and poultry. Creatine is phosphorylated by creatine kinase to the higher-energy phosphocreatine (41), which is used throughout the body as an energy source. Phosphocreatine is stored in more metabolically active areas, such as skeletal muscle, heart, and brain. Creatine supplementation first gained notoriety for its use as a performance enhancing supplement and has been used mainly in strength and muscle building activities (41).

Besides skeletal muscle, creatine is also used in the CNS as an energy source (21). In the animal model, creatine and phosphocreatine levels are decreased after mild TBI (98). Research has focused on the concept that creatine can replenish energy stores and minimize the effects of the hypermetabolic state that occurs after a cerebral concussion (103). Preclinical studies in rodents with a creatine rich diet have demonstrated some degree of neuroprotection follow experimental brain injury (91). Creatine neuroprotection may arise from maintenance of cellular ATP levels resulting in the reduction of mitochondrial permeability, free oxygen radicals, and calcium levels (103). The increase in mitochondrial membrane potential, decrease in intramitochondrial levels of ROS and calcium, and maintenance of adeosine triphosphate (ATP) levels suggest that neuroprotection is related to maintenance of mitochondrial bioenergetics (83).

In one study of severe pediatric TBI, creatine supplementation demonstrated improved short and long term outcomes (89). The improved short-term outcomes included less time intubated, less time in the intensive care unit (ICU), and improved amnesia. Long-term improvements were seen in self-care, communication, behavior, and cognition (89). These patients with TBI had injuries much more severe than a typical patient with SRC, and it is still unknown if improved outcomes would be seen in milder self-limited injuries, such as a concussion.

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Conclusion

Concussions are common neurologic events that affect many athletes. Very little has been studied on the treatment of concussions with supplements and medications. The U.S. FDA reminds us that no supplement has been proven to treat concussions (1). Many animal studies show that supplements have potential for improving the effects of a brain injury but none have been shown to be of consistent benefit in human studies. It is important to remember how vitamin E was thought to prevent cardiovascular disease in men but vitamin E was associated with an increased risk of hemorrhagic stroke and it seemed to increase mortality (18). Animal studies on severe TBI may not therefore be applicable transfer to SRC.

Of the many supplements reviewed in this article, Ω-3 FA have potential for SRC treatment but in the one human trial those taking higher dosages preinjury had more concussions and in animal studies postinjury administration was as effective as pretreatment. NAC has demonstrated a positive short-term effect on blast injuries in soldiers if administered within 24 h but there are no studies in SRC. Caffeine, conversely, may be detrimental if taken after SRC. Vitamins D, C, and E have the potential for efficacy if taken preinjury with lower serum levels suffering worse outcomes in animal studies. Current human trials for nicotinamide ribose, melatonin, and BCAA may soon provide more evidence for the use of these supplements to reduce the impact of SRC in athletes.

The authors declare no conflict of interest and do not have any financial disclosures.

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