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REVIEW ARTICLE
Year : 2012  |  Volume : 1  |  Issue : 1  |  Page : 27-36

Psychoactive nutraceuticals


1 Department of Psychiatry, Lady Hardinge Medical College, New Delhi, India
2 Department of Psychiatry, Post Graduate Institute of Medical Education and Research, Dr. Ram Manohar Lohia Hospital, New Delhi, India

Date of Web Publication3-Apr-2012

Correspondence Address:
Yatan Pal Singh Balhara
Department of Psychiatry and De-addiction, Lady Hardinge Medical College and Smt Sucheta Kriplani Hospital, New Delhi
India
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Source of Support: None, Conflict of Interest: None


DOI: 10.4103/2278-019X.94635

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  Abstract 

The term "nutraceutical" refers to foods with medical health benefit. Along with treatment, this benefit includes retardation of disease progression, enhancement of disease management, and effective risk factor modification. In spite of rather less frequent use of the term, nutraceuticals are increasingly being used in psychiatric practice. The current article presents an overview of the potential role and use of various nutraceuticals in psychiatric disorders. For purpose of the current review, the term "psychoactive nutraceuticals" has been used to represent nutraceuticals having specific mind-altering properties and found or claimed to be of benefit in psychiatric population.

Keywords: Nutraceuticals, psychoactive, S-adenosyl-L-methionine, Omega-3 fatty acids, psychiatry


How to cite this article:
Balhara YP, Verma R. Psychoactive nutraceuticals. J Med Nutr Nutraceut 2012;1:27-36

How to cite this URL:
Balhara YP, Verma R. Psychoactive nutraceuticals. J Med Nutr Nutraceut [serial online] 2012 [cited 2019 Jul 21];1:27-36. Available from: http://www.jmnn.org/text.asp?2012/1/1/27/94635


  Introduction Top


The term "nutraceutical" refers to foods with medical health benefit. Along with treatment, this benefit includes retardation of disease progression, enhancement of disease management, and effective risk factor modification. In spite of rather less frequent use of the term, nutraceuticals are increasingly being used in psychiatric practice. The current article presents an overview of the potential role and use of various nutraceuticals in psychiatric disorders. For purpose of the current review, the term "psychoactive nutraceuticals" has been used to represent nutraceuticals having specific mind-altering properties and found or claimed to be of benefit in psychiatric population.


  What are nutraceuticals? Top


The term "nutraceutical" was coined by Stephen DeFelice in 1989. It originated as combination of terms "nutrition" and "pharmaceutical". Over the years nutraceuticals have been defined differently. According to Brown (1998), a nutraceutical is "a food (or part of food) that provides medical or health benefits, including the prevention and/or treatment of a disease". [1] A more restrictive definition by Canada's Health Protection Bureau (HPB) defines it as "a product produced from food but sold in pills, powders (potions) and other medicinal forms not generally associated with food and demonstrated to have a physiological benefit or provide protection against chronic disease". [2]

Nutraceticals are also known as 'Dietary Supplements', 'Natural Health Products,' and 'Foods for Special Health Use (FOSHU)'. A dietary supplement as defined by Dietary Supplement Health and Education Act (DSHEA) is "a product (other than tobacco) that is intended to supplement the diet that bears or contains one or more of the following dietary ingredients: A vitamin, a mineral, an herb or other botanical, an amino acid, a dietary substance for use by man to supplement the diet by increasing the total daily intake, or a concentrate, metabolite, constituent, extract, or combinations of these ingredients; intended for ingestion in pill, capsule, tablet, or liquid form; not represented for use as a conventional food or as the sole item of a meal or diet; and includes products such as an approved new drug, certified antibiotic, or licensed biologic that was marketed as a dietary supplement or food before approval, certification, or license (unless the Secretary of Health and Human Services waives this provision)". [3]

A related concept of functional food is used to define "food being cooked or prepared using scientific intelligence with or without knowledge of how or why it is being used". This definition distinguishes functional food from nutraceuticals that are functional foods aiding in the prevention and/or treatment of disorders (other than anemia). [4] While some identify functional foods as a subclass of nutraceuticals, others, such as the HPB, consider functional foods to be a completely separate class of products. The term "nutraceutical" has not been recognized by FDA and these products continue to be subsumed under the broader rubric of "dietary supplements" in USA. [5]

The proposed draft of Food Safety and Security Act of India, 2006 has specified general properties and ingredients a nutraceutical product must have. These are specifically processed or formulated to satisfy particular dietary requirements which exist because of a physical or physiological condition or specific disease and disorder. Traditional medicines are not considered nutraceuticals as per the act.

Rationale for use of nutraceuticals

Dietary factors play an important role in premature chronic disease appearance, disease progression, morbidity and mortality. [6] Approximately 40-50% proportion in cardiovascular disorders, 35-50% proportion in cancers, and 20% proportion in osteoporosis is attributable to dietary factors. [7],[8]

Use of food as medicine for treatment and prevention of various disorders is not a recent development. Fortification of table salt with iodine and wheat flour with iron/folic acid has been used with specific aims of prevention of iodine deficiency goiter and anemia for long. Similarly, food fortified with vitamin A has been found to be a feasible and cost-effective approach to reduce vitamin A deficiency. A growing interest in relationship between diet and health has added impetus to the demand for information on nutraceuticals. This increased interest has been aided by advances in science and technology, increasing health care costs, changes in food laws affecting label, and product claims and aging population in various countries. Along with offering treatment, use of nutraceuticals favours a preventive treatment model as well.

Rationale for use of nutraceuticals in psychiatric disorders

Various psychiatric disorders have been conceptualized as the end result of interplay of host of biological, psychological and environmental factors. The vulnerability-stress diathesis model used to explain aetio-pathogenesis of these conditions highlights the importance of role of various external factors. With enhanced understanding in causal mechanisms for psychiatric disorders role of various biochemicals is being increasingly identified. This includes deficiency of various nutrients such as omega-3 fatty acids, various B-complex vitamins, minerals, and amino acids. [9],[10],[11] Causal role of serotonin deficiency in depression has been documented in various studies. [12] Tryptophan, an amino acid involved in synthesis of serotonin, has been found to be effective in treatment of this condition. Similarly, maternal deficiency of docosahexaenic acid (DHA) during pregnancy is associated with an increased prevalence of attention deficit/hyperactivity disorder (ADHD). [13] Around eight percent of individuals having bipolar illness have vitamin B deficiency. [14] Vitamin supplementation has been found to be effective in reducing depressive and manic features in these patients. [15] Increased consumption of refined sugar is associated with increased number of days spent in the hospital and poor social functioning among individuals diagnosed with schizophrenia. [16]

A correlation has been observed between the deterioration in dietary habits and increased prevalence of psychiatric disorders in western populations. [13],[17] Consumption of a diet rich in omega-3 fatty acids has been associated with a reduced prevalence of various psychiatric disorders including depression and schizophrenia. [16],[18]

Additionally, use of pharmacotherapeutic agents is not free of side-effects. Reduced need for these medications (by promoting prevention) as well as reduction in dosages needed for treatment (by using additional agents) would help reduce these undesired and troublesome side effects.

Nutraceuticals are of potential benefit in management of psychiatric disorders. The subsequent section describes role of various nutraceuticals in psychiatric disorders.

Omega-3 fatty acids (O3FAs)

O3FAs are essential long-chain polyunsaturated fatty acids (PUFA) obtained from dietary sources. [19] O3FAs competitively inhibit arachidonic acid. This leads to anti-inflammatory and anti-thrombotic effects by cytokine production. [20] They increase membrane fluidity by incorporation into the lipid bilayer. This facilitates neurotransmission by influencing receptor functioning and receptor-effector coupling. [21] Dampening of intracellular signal transduction caused by O3FAs has been hypothesized as the mechanism underlying their mood-stabilizing effect in bipolar disorders. [22]

O3FA levels have been reported to be low in psychiatric disorders. Several studies have suggested O3FA to be linked with ADHD symptoms and learning difficulties. [23] Deficiency of O3FAs leads to alterations in dopamine and serotonin neurotransmission and receptor density. [21] Epidemiologic studies suggest that greater fish consumption is associated with a lower prevalence of affective disorders. However, many of these studies have filed to account for the role of potential confounding factors. [9],[24],[25],[26],[27],[28]

PUFA may play an important role in the prevention and treatment of certain mental health disorders. [29],[30] Supplementation with combination of eicosapentaenoic acid (EPA) and docosahexaenoic acid (DHA) in children with reading writing disorder, dyspraxia and ADHD-related symptoms have reported significant symptom reductions. [31],[32] However, trials with DHA only have been less promising in this regard. [33]

A ceiling effect has been observed with O3FAs. These have been found to have a maximally effective dose when used in treatment of bipolar disorder and unipolar depression. In a meta-analysis of studies among individuals diagnosed with these conditions beneficial effect was observed with 1 g of EPA. Lesser efficacy was noted with higher doses. [34] It has been argued that O3FAs have only antidepressant rather than mood-stabilizing effect. In fact, use of O3FAs has been associated with emergence of mania and hypomania. [34] The available evidence does not support use of O3FAs as an alternative to standard pharmacological treatment in bipolar disorders. [35]

People with schizophrenia have been found to have low levels of essential fatty acids (EFAs) necessary for normal nerve cell membrane metabolism. [36],[37] Occurrence and course of schizophrenia is likely to be affected by dietary influences including levels of EFAs. [38] However, studies exploring role of O3FAs in treatment of schizophrenia have come up with mixed findings. [39] Most of these studies have failed to establish role of O3FAs in alleviating clinical features of schizophrenia. [34] Successive Cochrane reviews fail to support use of O3FAs in this condition. [40]

Animal studies have shown O3FAs administration to be associated with improved cerebral perfusion and cognitive performance. [41] However, these findings have not been consistently replicated in human studies. [42],[43],[44] There is evidence of an inverse relationship between fish or O3FAs intake and risk of dementia in observationa [42],[45] and epidemiological studies. [46],[47],[48],[49],[50],[51] However, a prospective cohort study by Moris et al., (2005) failed to replicate this association. [52] Similarly, the Canadian Study of Health and Aging did not find any beneficial effects from omega 3 PUFA. [43] Interventional studies assessing effectiveness of O3FAs in dementia are limited. They have been criticized for including smaller samples followed up for a shorter duration. [53] Cochrane review failed to make specific conclusions because of lack of data from randomized trials of dietary or supplemental O3FAs for the prevention of cognitive impairment or dementia. [54]

Safety of dietary or supplemental O3FAs with regards to total mortality, combined cardiovascular events or cancers in people with or at high risk of cardiovascular disease, and in the general population has been established in a Cochrane review. [55] These have been labeled as "generally regarded as safe" by FDA. [19] Some of the common side effects associated with use of fish oils include belching, halitosis, unpleasant taste and nosebleeds, nausea and vomiting in high dosage and blood glucose elevations in non-insulin-dependent diabetics. [19] Caution should be taken while using antiplatelet, anticoagulant drugs, or antihypertensive agents owing to their anti-platelet activity and ability to lower blood pressure. [56]

S-adenosyl-L-methionine (SAMe)

SAMe is a naturally occurring molecule present in body tissues and fluids. It is synthesized from L-methionine and adenosine triphosphate. [57],[58] It is an important donor of methyl group to a variety of molecules in body. Additionally, it is converted into adenosine and homocysteine. [59]

SAMe has been found to have analgesic and anti-inflammatory properties in animal studies. It is also believed to enhance receptor functioning or receptor-effector coupling. This action of SAMe is mediated through altering membrane fluidity by raising phosphatidylcholine levels in the lipid bilayer. [60] It also causes shifts in adrenergic and cholinergic receptor density, polyamine synthesis affecting intracellular signal transduction, and leads to changes in monoamine synthesis, turnover, and reuptake. [61]

A sizable literature supports role of SAMe as an antidepressant. [62],[63],[64],[65],[66],[67],[68] It has been found to be of comparable efficacy to a standard tricyclic antidepressant (TCA) in a placebo controlled comparative for treatment of depression. [69] A meta-analysis of comparative studies of SAMe with TCAs has supported these findings. [60] SAMe has also been suggested to be of use in shortening the onset of standard antidepressant therapy. [70]

SAMe is generally well tolerated. Common side effects reported with its use include nausea, vomiting, and diarrhea. Anxiety and restlessness have been reported in some patients with depression. SAMe induced switch to hypomania and mania have also been reported in some individuals with bipolar disorder. Serotonergic syndrome was reported in an elderly woman started on clomipramine and SAMe. [71] Individuals with preexisting movement disorders should be monitored closely when taking SAMe. Animal studies have reported SAMe-induced parkinsonian symptoms. [72] Increased monoamine methylation causing depletion of dopamine stores has been postulated as the underlying mechanism for this side effect. [72]

Dehydroepiandrosterone (DHEA)

DHEA and its sulfate ester (DHEA-S) are involved in production of estrogens and testosterone in body. [73] These are secreted by adrenal glands on stimulation by adrenal corticotropin-releasing hormone (ACTH). They enhance the effects of glutamate (an excitatory neurotransmitter) and decrease the effects of GABA (an inhibitory neurotransmitter). [74],[75] They have been postulated to have a neuroprotective effect. Studies have suggested an increase in level of DHEA and DHEA-S in stress associated with exercise and reduction in level in disease states. [76],[77]

Studies have reported reduced serum levels of DHEA or DHEA-S in dementia patients. [78],[79],[80] However, some others have failed to replicate these findings. [81],[82] Cochrane review exploring beneficial effect of DHEA supplementation on cognitive function of non-demented middle-aged or elderly people was inconclusive due to contradictory evidence from studies included in the analysis. [83]

Studies in unmedicated patients with schizophrenia and children with depression have shown reduced DHEA levels. [84],[85],[86] These findings suggest possible role of these agents in management of schizophrenia and depressive disorders. [87],[88]

DHEA and DHEA-S can lead to weight gain, voice changes, hirsutism, menstrual irregularities, and headaches in females and gynaecomastia or prostatic hypertrophy in males due to their association with elevated androgen and estrogen levels in body. Use of larger doses of DHEA was found to be associated with elevations in transaminases and lactate dehydrogenase. However, no notable hepatotoxicity was observed in these studies. [89],[90] The safety of DHEA supplements in hormone-sensitive tumors has not been established. [91]

Vitamins

Role of various vitamins in maintaining normal metabolism and health status has been well researched. Deficiencies in niacin, thiamine, vitamin B12, and folate are known to have adverse neuropsychiatric effects. [92] Some vitamins are necessary for synthesis of other nutraceuticals. For example, folate and vitamin B12 are necessary for the formation of SAMe. [19]

A higher prevalence of psychiatric disorders in elderly patients with folate deficiency has been reported. An association has been observed between folate deficiency and psychiatric disorders including schizophrenia, depression and organic psychosis. [93],[94],[95] Folate supplementation has been found to be effective when used in addition to conventional antidepressant medications. [96]

Low serum folate levels have been associated with Alzheimer's disease and other types of dementia. [97],[98] Prospective studies have also reported low folate levels as a risk factor for dementia. [99],[100] Older people with low folate status are more likely to be demented, institutionalized or depressed (Ebly 1998). [98] High homocysteine levels are associated with a decrease in cognitive function and dementia. Significant decline in blood total homocysteine levels can be achieved by administration of folate. [101] This finding also supports role of folate in cognitive enhancement.

However, a recent Cochrane review failed to establish role of folic acid, with or without vitamin B12, in improving cognitive function of unselected healthy or cognitively impaired older people. [102] Recently, there have been concerns about increase in colorectal cancer with introduction of folic acid into the food chain in USA. [103]

No evidence of the efficacy of vitamins B1, B6 or E for people with Alzheimer's disease has been established.

Minerals

Calcium dysregulation is reported to be important in disorders such as dementia and depression. [104],[105],[107] Dietary calcium has been found to promote learned helplessness in animal studies. [108] Studies among patients with depressive disorder, schizophrenia and substance abuse have reported a higher prevalence of calcification and disturbances of calcium metabolism. [104],[109]

Micronutrient (e.g., iron, magnesium and zinc) intake has been linked to structural as well as functional development of brain. [110] Beneficial effect of magnesium and zinc consumption on attention, executive functions, behavioural, and emotional problems of children and adolescents has been observed. [111],[112] Low zinc levels are correlated with inattentiveness symptoms in children with attention deficit/hyperactivity disorder (ADHD). [113] Micronutrient supplementation improved attention-concentration symptoms in school children having ADHD. [114] Decreased plasma and erythrocyte magnesium levels and decreases in Mg 2+ -ATPase activity has been observed in children with ADHD. [115]

Huperzine-A

Huperzine is derived from clubmoss Huperzia serrata. [116] It has been recognized as a potent reversible inhibitor of acetylcholin-esterase (AChE). [117]

Use of huperzine in the treatment of patients suffering from Alzheimer's disease (AD) and various other memory disorders has been found to be associated with positive response. [118],[119],[120],[121] Its use has been reported to enhance the memory and learning performance of adolescent students. [122] It is likely that Huperzine-A has a potent neuroprotective action not only where cholinergic neurons are impaired but also under conditions in which the production of glutamate is compromised. Because of this it appears to be safe, well tolerated, and effective in the symptomatic treatment of AD. [123],[124] Huperzine A has been reported to have beneficial effects on improvement of general cognitive function, global clinical status, behavioral disturbance, and functional performance in AD in a Cochrane review. [125] No major side effects have been reported with its use.

Choline

Choline is present in almost every tissue in the body. It is essential for normal function of all cells. It maintains the structural integrity of cell membranes and is a source of methyl-groups. It also affects nerve signaling, cell signaling and lipid transport and metabolism.

Hippocampal choline acetyltransferase activity is correlated with the extent of Alzheimer's disease lesions. [126] Cholinergic dysfunction and deposition of beta-amyloid peptide leads to cognitive impairment associated with AD. Studies report improvement in immediate and delayed recall on verbal memory in dementia subjects and healthy elderly subjects when given citicoline. [127]

N-acetyl cysteine (NAC)

N-acetyl cysteine NAC is the N-acetyl derivative of cysteine. It is comparativle less reactive, less toxic and less susceptible to oxidation than its parent molecule. NAC inhibits synaptic glutamate release through glial cystine-glutamate exchange. Cysteine is found in a number of high protein foods. However, NAC is not usually obtained from dietary sources and must be added as a supplement. [128]

Since NAC reduces oxidative stress and inflammation, it is expected to be useful in treating psychiatric disorders. [129] Case reports support its beneficial effects in obsessive compulsive spectrum disorders. [130],[131],[132] Additionally, a double-blind randomized placebo-controlled trial in trichotillomania reported a significantly greater reduction in hair-pulling symptoms in NAC treatment group as compared to placebo. [133]

Acetyl-L-Carnitine

Acetyl-L-Carnitine (ALC) is derived from carnitine. It has interaction with acetylcholine, fatty acids, and phospholipids. This is responsible for its activity at cholinergic neurons, membrane stabilization and enhancing mitochondrial function.

Some studies have suggested slowing down of declining cognitive functions in mild Alzheimer's disease or mild cognitive impairment. However, others have failed to find any significant difference in placebo controlled trials. [134] A recent meta-analysis found that of 21 studies conducted, 17 showed that it had a positive effect on patients with mild cognitive impairment or mild AD. [135]

Cochrane review reports evidence for benefit of ALC on clinical global impression and MMSE at 24 weeks. However, lack of evidence of its effectiveness assessed by objective measures in any other area of cognitive outcome suggests that statistically significant results might be a chance finding. [136]

Acetyl-L-carnitine appears to have been well tolerated at doses of 1.5-3 g/day in various studies. Side-effect profiles appear to have been similar to those of placebo, with reports of body odor, increased appetite, rash, and restlessness. [134],[135]

Phosphadtidylserine and phosphatidylcholine

Phosphatidylserine and phosphatidylcholine are phospholipids of plant and bovine origin. Research on these substances has produced mixed findings. Researchers have found that phosphatidylserine had a significant effect on cognitive functioning. However, the studies have been criticized for using small sample size. [137] One placebo controlled study with a formulation of phosphatidylserine among individuals having age-associated memory impairment reported improvement on performance tests related to learning and memory and tasks of daily life. [138] However, another study by Jorrison et al., (2001) failed to find any significant positive effects. [139] In a review of clinical trials of the efficacy of phosphatidylserine, Kidd (1999) concluded that phosphatidylserine provides significant improvements in memory, learning, concentration, word recall, and mood in individuals with age-related cognitive decline. [140]

Tryptophan and 5-HTP

The essential amino acid tryptophan or its hydroxylated form 5-hydroxytryptophan (5-HTP) can be used for enhancing serotonergic transmission in the central nervous system (CNS). Conversion of exogenous tryptophan from dietary sources is the source of 5-HTP in human body. Only about 2% of ingested tryptophan is used for 5-HT synthesis in brain. [141] Moreover, tryptophan competes with other large neutral amino acids to penetrate the blood brain barrier. [142] This limits the potential use of orally administered tryptophan to boost brain levels of 5-HT.

Research indicates that 5-HTP may be a useful strategy in the treatment of depression. [143],[144],[145] However, clinical trials of tryptophan or 5-HTP administration have given conflicting results in other studies. Some reviewers have found both substances to have an antidepressant effect. [146],[147] Other reviewers have found the evidence supporting use of tryptophan and 5-HTP for depression to be weak at best. [148] Cochrane review on 5-HTP use in depression was inconclusive reporting difficulty to recommend or discourage its use. [149] A recent study by Gendle and Golding (2010) in adults provided evidence to suggest that oral 5-HTP is psychoactive at a low 100 mg oral dose and has significant effects on cognition. [150]

Drug naive patients with Obsessive Compulsive Disorder (OCD) have been found to have lower plasma levels of tryptophan. [151] However, experimentally-induced tryptophan depletion has not been found to lead to worsening of OCD symptom severity. [152]

Preclinical research as suggested that prolonged tryptophan supplementation may lead to elevated levels of brain oxidative stress. [153] This, in turn, can escalate the underlying damage process in psychiatric disorders.

Nutraceuticals have been postulated to be of potential use in psychiatric disorders. Their role has been explored in conditions such as schizophrenia, major depression, dementia and OCD. However the literature continues to be limited for most of these agents. Mutually conflicting evidence makes it difficult to recommend or preclude use of these agents in various psychiatric disorders. There is a need to assess nutraceuticals in a systematic manner to establish conclusive evidence. Well-planned randomized placebo controlled trials would help find definitive answers in this regard.

 
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