Neuropsychiatric outcomes of nutraceuticals
Enzogenol. This flavonoid-rich extract from the bark of the Monterey pine tree (Pinus radiata), known by the trade name Enzogenol, reportedly has antioxidant and anti-inflammatory properties that may counter oxidative damage and neuroinflammation following TBI. A phase II trial randomized participants to Enzogenol, 1,000 mg/d, or placebo for 6 weeks, then all participants received Enzogenol for 6 weeks followed by placebo for 4 weeks.33 Enzogenol was well tolerated with few side effects.
Compared with placebo, participants receiving Enzogenol showed no significant change in mood, as measured by the Hospital Anxiety and Depression Scale, and greater improvement in overall cognition as assessed by the Cognitive Failures Questionnaire. However, measures of working memory (digit span, arithmetic, and letter–number sequencing subtests of the Wechsler Adult Intelligence Scale) and episodic memory (California Verbal Learning Test) showed no benefit from Enzogenol.
Citicoline (CDP-choline) is an endogenous compound widely available as a nutraceutical that has been approved for TBI therapy in 59 countries.34 Animal studies indicate that it could possess neuroprotective properties. Proposed mechanisms for such effects have included stabilizing cell membranes, reducing inflammation, reducing the presence of free radicals, or stimulating production of acetylcholine.35,36 A study in rats found that CDP-choline was associated with increased levels of acetylcholine in the hippocampus and neocortex, which may help reduce neurobehavioral deficits.37
A study of 14 adults with mild to moderate closed head injury38 found that patients who received CDP-choline showed a greater reduction in post-concussion symptoms and improvement in recognition memory than controls who received placebo. However, the Citicoline Brain Injury Treatment Trial, a large randomized trial of 1,213 adults with complicated mild, moderate, or severe TBI, reported that CDP-choline did not improve functional and cognitive status.39
Physostigmine and lecithin. The cholinergic system is a key modulatory neurotransmitter system of the brain that mediates conscious awareness, attention, learning, and working memory.40 A double-blind, placebo-controlled study of 16 patients with moderate to severe closed head injury provided inconsistent evidence for the efficacy of physostigmine and lecithin in the treatment of memory and attention disturbances.41The results showed no differences between the physostigmine–lecithin combination vs lecithin alone, although sustained attention on the Continuous Performance Test was more efficient with physostigmine than placebo when the drug condition occurred first in the crossover design. The lack of encouraging data and concerns about its cardiovascular and proconvulsant properties in patients with TBI may explain the dearth of studies with physostigmine.
Cerebrolysin. A peptide preparation produced from purified pig brain proteins, known by the trade name Cerebrolysin, is popular in Asia and Europe for its nootropic properties. Cerebrolysin may activate cerebral mechanisms related to attention and memory processes,42 and some data have shown efficacy in improving cognitive symptoms and daily activities in patients with Alzheimer’s disease43 and TBI.44
A blinded 12-week study of 32 participants with acute mild TBI reported that those randomized to Cerebrolysin showed improvement in cognitive functioning vs the placebo group.45 The authors concluded that Cerebrolysin provides an advantage for patients with mild TBI and brain contusion if treatment starts within 24 hours of mild TBI onset. Cerebrolysin was well tolerated. Major limitations of this study were small sample size, lack of information regarding comorbid neuropsychiatric conditions and treatments, and short treatment duration.
A recent Cochrane review of 6 RCTs with 1,501 participants found no clinical benefit of Cerebrolysin for treating acute ischemic stroke, and found moderate-quality evidence of an increase with non-fatal serious adverse events but not in total serious adverse events.46 We do not recommend Cerebrolysin use in patients with TBI at this time until additional efficacy and safety data are available.
Nutraceuticals used in other populations
Other nutraceuticals with preclinical evidence of possible benefit in TBI but lacking evidence from human clinical trials include omega-3 fatty acids,47 curcumin,48 and resveratrol,49 providing further proof that results from experimental studies do not necessarily extend to clinical trials.50
Studies of nutraceuticals in other neurological and psychiatric populations have yielded some promising results. Significant interest has focused on the association between vitamin D deficiency, dementia, and neurodegenerative conditions such as Alzheimer’s disease, multiple sclerosis, and Parkinson’s disease.51 The role of vitamin D in regulation of calcium-mediated neuronal excitotoxicity and oxidative stress and in the induction of synaptic structural proteins, neurotrophic factors, and deficient neurotransmitters makes it an attractive candidate as a neuroprotective agent.52
RCTs of nutraceuticals also have reported positive findings for a variety of mood and anxiety disorders, such as St. John’s wort, S-adenosylmethionine, omega-3 fatty acids for major depression53 and bipolar depression,54 and kava for generalized anxiety disorder.55 More research, however, is needed in these areas.
The use of nonpharmacologic agents in TBI often relies on similar neuropsychiatric symptom profiles of idiopathic psychiatric disorders. Attention-deficit/hyperactivity disorder (ADHD) closely resembles TBI, but systemic reviews of studies of zinc, magnesium, and polyunsaturated fatty acids supplementation in ADHD provide no evidence of therapeutic benefit.56-58
Educate patients in role of nutraceuticals
Despite lack of FDA oversight and limited empirical support, nutraceuticals continue to be widely marketed and used for their putative health benefits59 and have gained increased attention among clinicians.60 Because nutritional deficiency may make the brain less able than other organs to recover from injury,61 supplementation is an option, especially in individuals who could be at greater risk of TBI (eg, athletes and military personnel).
Lacking robust scientific evidence to support the use of nutraceuticals either for enhancing TBI recovery or treating neuropsychiatric disturbances, clinicians must educate patients that these agents are not completely benign and can have significant side effects and drug interactions.62,63 Nutraceuticals may contain multiple ingredients, some of which can be toxic, particularly at higher doses. Many patients may not volunteer information about their nutraceutical use to their health care providers,64 so we must ask them about that and inform them of the potential for adverse events and drug interactions.