General Health
Emotional Wellness
Heather Granato - naturalproductsinsider.com
Aug 16, 2004, 10:20

Mental illness, including suicide, accounts for more than 15 percent of the burden of disease in established market economies, such as the United Statesmore than the disease burden caused by all types of cancers. With more than 22 percent of Americans suffering from a diagnosable mental disorder in a given year, it is no wonder that sales of pharmaceuticals to treat depression and anxiety are on the rise. However, there is increasing knowledge of the role nutrients may play in regulating mood and health.

The pervasive nature of mental disorders has made it a ripe area for film depictions. Consider how obsessive-compulsive disorder (OCD) played a role in As Good As It Gets, the way Ingrid Bergman was driven to agoraphobia and social anxiety in Gaslight and the image of Winona Ryder institutionalized in Girl, Interrupted. But even these character studies can fail to capture the disabling nature of mental disorders.

Consider that four of the 10 leading causes of disability in the United States and other developed countries are mental disordersmajor depression, bipolar disorder, schizophrenia and OCD.

The main depressive disorders are major depression, dysthymic disorder and bipolar disorder. According to the National Institute of Mental Health (NIMH), almost 10 percent of the U.S. population age 18 and older suffers a depressive disorder in a given year, with nearly twice as many women afflicted as men. In fact, depression is the leading cause of disability adjusted life years (DALYs) among all women; DALYs measure lost years of healthy life. NIMH further noted depressive disorders appear to be happening earlier in life today than in decades past.

Anxiety disorders are also included in the umbrella of mental disorders and, as a group, are the most common mental illness in America. NIMH estimates approximately 13.3 percent of adults between 18 and 54 have an anxiety disorder in a given year. These include panic disorder, OCD, post-traumatic stress disorder and phobias (i.e., agoraphobia, social phobia). Again, women are more likely to suffer anxiety disorders, though OCD and social phobia strike the sexes equally.

While depression and anxiety disorders are becoming increasingly common, fewer patients are receiving adequate therapy. A nationally representative study of more than 9,000 Americans found about 57 percent of participants with major depression had received treatment, up from 17 percent in the early 1980s.1 However, treatment was considered adequate or adhered to acceptable guidelines in only 21 percent of patients with recent depression.

Fortunately, many types of natural compounds are proving adept at enhancing the impact of pharmaceutical treatments (including selective serotonin reuptake inhibitors, SSRIs) and at treating underlying nutrient deficiencies that may affect mental functioning. In a 2002 review study from the Australian National University, Canberra, researchers identified 37 different complementary and self-help treatments for depression.2

They found St. Johns wort, exercise, cognitive behavior therapy and light therapy had the best support, while S-adenosylmethionine (SAMe) and folate also appeared promising in treatment of depressive conditions.

Folate levels have been shown to be low in depressed individuals. A study of an ethnically diverse U.S. population sample (n=2,948) found subjects who met criteria for a lifetime diagnosis of major depression had lower plasma folate levels than individuals who had never been depressed.3 Another study in Finland examined 2,682 men between 42 and 60, and found those in the lowest third of folate intake had a higher risk of being depressed than those individuals with the highest folate intake.4

The link between folate and depression has lead researchers to speculate treatment with folate could enhance pharmaceutical treatment of depression. A Cochrane Database System review of trials involving folate and antidepressants concluded, folate may have a potential role as a supplement to other treatment for depression.5

Researchers from New York University Medical Center compared the effects of two types of antidepressant pharmaceuticals in depressed geriatric patients, and found higher folate levels at baseline predicted a greater improvement in depression scores.6 Another placebo-controlled study from West Park Hospital in Surrey, England, examined the effect of 500 mcg/d on the efficacy of 20 mg/d of the pharmaceutical fluoxetine.7

Patients receiving folate showed a significant increase in plasma folate, a significant decrease in homocysteine and a greater improvement in depression scores in the folate/pharmaceutical treatment group. The researchers noted folic acid could greatly improve the action of antidepressants, but should be given in sufficient doses to decrease plasma homocysteine.

The homocysteine link to depression has been examined in other studies. A study from the University of Bergen, Norway, examined the association between homocysteine, folate and vitamin B12 in almost 6,000 subjects.8 The researchers found hyperhomocysteinemia was significantly related to depression, though low folate or B12 levels were not. The exception was a link between low folate and depression in middle-aged women. In another population study, Dutch researchers screened 278 elderly people with depressive symptoms compared to 416 reference subjects.9 They found hyperhomocysteinemia, vitamin B12 deficiency and, to a lesser extent, folate deficiency were all related to depressive disorders. The researchers concluded vitamin B12 deficiency may be causally related to depression, while low folate may be due to a physical comorbidity.
Sales of Products for Emotional Health
Mainstream and natural products channel sales numbers are for the 52 weeks ending May 15, 2004, in Mainstream Food/Drug/Mass Combo distribution channels and in Natural Product Supermarkets.

Similarly, a Finnish study examined whether there were associations between vitamin B12 and folate levels and six-month treatment outcomes in 115 patients with major depressive disorder.10 The researchers found higher B12 levels were significantly associated with a better outcome, leading them to conclude B12 levels are positively linked to the probability of recovery from depression.

Another part of the B complex family is inositol, which is required for proper formation of cell membranes and affects nerve transmission. A recent Cochrane Database System review of trials examining the use of inositol for depressive disorders concluded it is unclear whether inositol is beneficial in treating depression, but further studies should clarify the situation.11 However, studies have shown some benefit. A rat study conducted at Ben Gurion University of the Negev in Beer Sheva, Israel, found rats that received 1.2 g/kg of inositol for 14 days prior to a forced swim test countered the immobility of rats that received placebo.12 And in a double blind, crossover study in 20 patients with panic disorder, researchers found 18 g/d reduced the number of panic attacks as well as the pharmaceutical fluvoxamine.13 The researchers, also from Ben Gurion University, noted inositol is attractive to patients who are ambivalent about taking medication because it is a natural substance.

Another basic nutrient studied in depressive disorders is chromium. A number of studies have investigated the use of the mineral in treatment of atypical depression, as the low brain serotonin levels found in this condition may be linked to insulin sensitivity. A report from the University of North Carolina School of Medicine, Chapel Hill, noted eight patients with refractory mood disorders received supplementation with chromium picolinate (as Chromax from Purchase, N.Y.-based Nutrition 21) and found improvements in the patients symptoms and functioning.14 They suggested chromium acted by enhancing insulin utilization and subsequently increasing tryptophan levels in the central nervous system.

Further research into chromium picolinate for depression has shown positive results. A placebo-controlled, double blind study was conducted at Duke University Medical Center in Durham, N.C., investigating the effects of 600 mcg/d of chromium picolinate (as Chromax) on patients with atypical depression.15 The researchers found 70 percent of the chromium group responded to treatment, compared with none of the placebo group. The results of this pilot study led to development of a multi-center, eight-week double blind study of 113 patients with atypical depression.16 Researchers found supplementation with 600 mcg/d of chromium picolinate (as Chromax) significantly reduced some key symptoms of atypical depression, including carbohydrate cravings, mood swings and fatigue. Subjects with the highest levels of carbohydrate cravings reported the most significant reduction in depressive symptoms.

Another compound mentioned in the Australian review as efficacious in depression is S-adenosylmethionine (SAMe). A review out of Massachusetts General Hospital in Boston noted SAMe has been extensively studied for its antidepressant efficacy.17 SAMe is a methyl donor involved in the synthesis of several neurotransmitters, and studies have shown doses of 200 mg/d to 1,600 mg/d are superior to placebo and as effective as tricyclic antidepressants in alleviating depression.18 While its method of action is unclear, a rat study suggested SAMe may normalize levels of specific neurons, including putrescine, in the brain.19 Also, researchers at Harvard Medical School in Boston gave 1,600 mg/d of oral SAMe to 12 subjects, and found SAMe altered phosphocreatine levels and parameters associated with brain bioenergetics.20

SAMes efficacy has also been tested, both through intramuscular and oral delivery methods. A study from Universita La Sapienza, Rome, compared the efficacy of 400 mg/d of intramuscular SAMe against 150 mg/d oral imipramine (IMI) in patients with major depression.21 SAMe and IMI did not differ significantly on any efficacy measure, but patients treated with SAMe had significantly fewer adverse events. Another study from the same researchers compared the effects of 1,600 mg/d of oral SAMe with the same intramuscular SAMe and oral IMI doses.22 The study confirmed the oral SAMe dosage had the same efficacy as the intramuscular dose, also with better tolerance compared to IMI.

Nutrients that impact neurotransmitters have been closely studied for their possible applications in treating depression. Several naturally occurring nutrients directly linked to the brains production of neurotransmitters have also been investigated as dietary supplements. One such nutrient is 5-hydroxy-L-tryptophan (5-HTP), the immediate precursor in the biosynthesis of serotonin from the amino acid L-tryptophan. While L-tryptophan was banned as a dietary supplement in 1989 after an outbreak of eosinophilia-myalgia syndrome (EMS) was linked to contaminated synthetic L-tryptophan, 5-HTP is marketed as a supplement in the United States. A 2004 research review noted there have been no definitive cases of toxicity linked to 5-HTP use in the last 20 years, nor have toxic contaminants been found.23 However, a 2002 Cochrane Database System review noted while evidence suggests 5- HTP is better than placebo at alleviating depression, further studies are needed to confirm its safety.24

However, 5-HTP is being studied for its usefulness in both depression and anxiety. One study out of Maastricht University, The Netherlands, examined the reaction of 24 panic disorder patients and 24 healthy volunteers to a 35-percent carbon dioxide panic challenge after administration of 200 mg of 5-HTP or placebo.25 5-HTP significantly reduced the reaction to the panic challenge in panic disorder patients, though no effect was observed in healthy volunteers. The researchers suggested 5-HTP acts to modulate serotonin in panic disorder.

A proprietary extract of Griffonia simplicifolia seed (as Serotain from Wayne, N.J.-based Triarco Industries) has been studied as a natural 5-HTP source. Company studies have shown Serotain does not inhibit monoamine oxidase, but is specific for the serotonin transport (reuptake) system. In addition, the concern expressed in some research studies about Peak X in synthetically produced 5-HTP is eliminated because of the natural source for Serotain; also, Serotain was analyzed by two laboratories to confirm it is Peak X negative.

Another hormone product related to mood is melatonin. This pineal hormone regulates many body functions and exhibits a circadian release pattern in the bodyhigher at night and low in the morning. Alterations in its secretory pattern have been found in disorders including seasonal affective disorder (SAD), bulimia, schizophrenia, panic disorder and OCD; however, the pathophysiology involved in each disorder is relatively unknown.26 Further, a study from the Himalayan Institute of Medical Sciences showed high morning melatonin levels in patients suffering from depression decreased during pharmacological treatment.27

Many studies have examined the relationship between SAD and melatonin levels. A small study at the University of Iceland, Reykjavik, compared melatonin concentrations in patients with and without SAD.28 The concentration of melatonin in SAD patients was on average 2.4 times as high as in the control group. Another trial investigated the effects of 2 mg of sustained release melatonin or placebo before bedtime in 58 healthy adults with SAD and/or weather-associated syndrome (WAS).29 Melatonin administration significantly improved the quality of sleep and vitality in patients with SAD, but attenuated improvement of quality of life in subjects with positive-type WAS.

Other studies have examined melatonins impact on depression and anxiety. A rat study conducted at the Panjab University in Chandigarh, India, investigated the effect of melatonin on the forced swimminginduced behavioral despair test.30 While acute administration of higher doses of melatonin did not induce anti-depressant activity in mice subjected to the test the first time, daily administration of melatonin prior to the test had a positive impact on mice chronically exposed to the test. The researchers concluded melatonin had anti-depressant action, possibly by impacting GABA-benzodiazepine receptors. In another rat study, researchers examined whether melatonin could reverse increased anxiety levels linked to injection of E. coli lipopolysaccharide.31 They found prior, concomitant and subsequent treatment with 4 mg/kg or 6 mg/kg of melatonin all worked to reverse the anxiety effect.

DHEA (dehydroepiandrosterone) is another hormone that also functions as a neurosteroid. A review from the Harvard-MIT Division of Health Sciences and Technology in Cambridge, Mass., noted evidence shows DHEA supplementation may help in many conditions including schizophrenia and depression.32 Another review noted while DHEA supplementation may be helpful in depressive illnesses, treatment should be undertaken under medical supervision to keep watch for hormone-dependent cancers of the breast or prostate.33

DHEAs action in depressed patients is suggested to result from enhancement of noradrenaline and serotonin neurotransmission and/or moderation of glucocorticoids, which can adversely affect cognition.34 A clinical study at the University of Newcastle upon Tyne, England, examined the ratio of the stress hormone cortisol to DHEA in drug-free depressed patients and a matched comparison group.35 They found the molar cortisol-DHEA ratio was significantly higher in depressed patients, and that elevated ratio could contribute to neurocognitive deficits seen in patients with major depression. A twoyear longitudinal study of 60 adolescents at high risk of psychiatric disorders also examined the impact of cortisol and DHEA, and found patients with persistent major depression had a raised morning cortisol/DHEA ratio.36

Beneficial compounds for mood enhancement are not limited to hormones or vitamins. In fact, recent research on essential fatty acids (EFAs) has investigated the importance of EFAs for mental health. Since the 1970s, population studies have shown lesser incidences of anxiety and depressive disorders in populations with a higher intake of omega-3 EFAs. The importance of EFAs to mental health can be seen in the way native peoples have responded to a more modern diet with less omega-3 and more of the inflammatory omega-6. A study from the University of Alaska Fairbanks reviewed information on the change to traditional diets among people in the Arctic and Subarctic environments.37 They found the change to more processed foods and Western dietary habits has not only increased the rate of cardiovascular disease, obesity and diabetes among these people, but has also caused a concurrent increase in depression and anxiety.

Similarly, population-based trials have examined intake of omega-3 fatty acids and rates of mental disorders. Researchers from the University of Kuopio, Finland, examined data from a sample of 3,204 Finnish adults and found the likelihood of depression was significantly higher among infrequent fish consumers than among frequent consumers.38 However, a larger trial in Finland, conducted by the National Public Health Institute, did not find an association between dietary intake of omega-3 fatty acids and mood.39

Other population-based studies support the earlier Finnish researchers. In the Rotterdam Study, conducted at Erasmus Medical Centre, The Netherlands, researchers screened 3,884 adults over 60 years old for depressive syndromes.40 Percentages of omega-3 and omega-6 EFAs were compared in 264 subjects with depressive symptoms and 461 reference subjects. Those people with depressive disorders had a higher ratio of omega-6 to omega-3 EFAs, suggesting fatty acid composition may impact mood. Similarly, a study of 150 elderly males from Crete found depressed subjects had significantly reduced adipose tissue alpha-linolenic acid (C18:3n-3) compared to nondepressed subjects.41 The researchers noted depression is associated with elevated inflammatory cytokines, while omega-3 EFAs appear to inhibit cytokine production.

Omega-3s are also critical to cardiovascular health, and studies have investigated the connection between cardiovascular disease, homocysteine levels and omega-3 EFA intake. A review of studies in this area suggested omega-3 deficiency and elevated homocysteine levels are possibly related factors that have a causal relationship with depressive disorders and cardiovascular disease.42 A recent pilot study from the Academic Medical Centre in Amsterdam, The Netherlands, studied homocysteine and fatty acid levels in 44 patients with major depressive disorders.43 They found a significant association between total omega-6 EFAs and plasma homocysteine, as well as decreased levels of some omega-3s and omega-9s in the plasma. Further, a casecontrolled study of serum EFA levels and current major depression in 54 age- and sex-matched pairs two months after coronary syndromes found depressed patients had significantly lower total omega-3 and DHA (docosahexaenoic acid, the longest-chain omega-3) levels and higher levels of arachidonic acid and omega-6s.44

The omega-3 EPA (eicosapentaenoic acid) has been independently studied for its impact on depressive conditions. One study was conducted at Swallownest Court Hospital in Sheffield, England, and involved 70 patients with persistent depression despite ongoing treatment with a standard antidepressant.45 Patients were randomized to receive 1 g/d, 2 g/d or 4 g/d of ethyl-EPA or placebo for 12 weeks in addition to their medication. The 1 g/d EPA group showed a significantly better outcome than the placebo group in depression outcomes, while the 2 g/d group had almost no impact and the 4 g/d level had a nonsignificant trend toward improvement. Another study investigated the effect of 2 g/d of EPA plus an SSRI on OCD, but found no benefit to adjunctive use of EPA.46 Finally, an eight-week, placebo controlled, double blind study at McLean Hospital in Belmont, Mass., investigated the impact of 1 g/d of EPA on 29 female subjects with borderline personality disorder.47 EPA was superior to placebo in diminishing aggression as well as severity of depressive symptoms.

Botanical Compounds

As most mood disorders respond to pharmacologically active compounds, it is unsurprising that several botanical and plant extracts have been studied for their impact in this realm. One review of herbal medicines used for psychiatric disorders examined trials on three of the most commonly discussed botanicalsSt. Johns wort, kava and valerian.48 The researchers found the controlled and standardized trials of St. Johns wort seemed evenly split on the herbs efficacy compared to placebo. Kava was seen to have demonstrated anxiolytic efficacy, but the researchers noted the trials were generally conducted in small populations for a short duration. Finally, valerian was said to improve subjective sleep quality, but benefits generally took two to four weeks of therapy.

St. Johns wort (Hypericum perforatum) has been singled out as the most studied botanical for treating mild to moderate depression, and is used for this purpose as a pharmaceutical in Europe. The active constituent is generally considered to be the lipophilic constituent hyperforin, which has been seen to operate similar to an SSRI, inhibiting the uptake of serotonin.49 A review of its actions and side effects suggest in addition to blocking the reuptake of serotonin, noradrenaline and dopamine, it may also inhibit monoaminoxidase (MAO) enzyme activity and increase the density of serotonergic and dopaminergic receptors.50

A 2002 meta-analysis performed at the University of Vienna, Austria, reviewed the original data of three double blind, randomized multicenter trials involving a total of 544 patients with mild to moderate depression.51 Hypericum extract was found to reduce both core symptoms of depression and depression-related anxiety and insomnia more effectively than placebo. The general effects on all aspects of depression led the researchers to conclude St. Johns worts therapeutic profile may be similar to that of SSRIs. Another meta-analysis, released in June 2004, incorporated data from 30 studies, and found St. Johns wort had a significant advantage compared to placebo and similar effectiveness compared to synthetic antidepressants.52 In fact, in studies of mild to moderate depression, St. Johns wort posted better results than synthetic antidepressants, leading the researchers to suggest use of the herb first for milder forms of depression.

However, the efficacy of St. Johns wort is increasingly in question, a process that began with the publication of a study in 2002 investigating the effect of St. Johns wort on major depressive disorder.53 In the eight-week study, patients received 900 mg/d to 1,500 mg/d of H. perforatum, 50 mg/d to 100 mg/d of the pharmaceutical sertraline or a placebo. Neither St. Johns wort nor sertraline was shown effective in the study for major depression; however, most news reports focused exclusively on the botanicals results without mentioning the drugs lack of impact. And another meta-analysis, released in May 2004, compared data on 18 studies and concluded St. Johns wort may be less effective in the treatment of depression than previously assumed and may finally be shown to be ineffective if future trials confirm this trend.54

The interesting dichotomy between meta-analyses raises questions about the severity of depression that can be treated with St. Johns wort, as well as the comparable successful use of pharmaceutical agents. In a 2003 analysis published in Complementary and Therapeutic Medicine, Irving Kirsch, Ph.D., examined the issue.55 The efficacy of antidepressant medication is generally thought to be well established, whereas that of hypericum (St. Johns wort) is considered doubtful. The data fail to support these discrepant conclusions. Instead they show that hypericum and conventional antidepressants are equally effective (or ineffective). This suggests that different standards are being used to evaluate the two types of treatment.

Regardless of the level of efficacy, St. Johns wort has been shown to have pharmacological activity in the body, which has raised questions regarding its ability to interact with prescription pharmaceuticals. A recent research review noted St. Johns wort has been shown to lower the plasma concentration and/or efficacy of a number of drugs, including cyclosporine, digoxin, indinavir, simvastatin, warfarin and oral contraceptives.56 The researcher noted induction of P-glycoprotein and/or cytochrome P450 enzymes could explain St. Johns worts effects.

Another relatively controversial botanical used in treatment of mood disorders is kava (Piper methysticum). A Cochrane Database System review released in 2003 assessed the safety and efficacy of kava extract in treating anxiety.57 Eleven trials with a total of 645 participants were included; a meta-analysis of six studies using a common outcome measure found a significant reduction in anxiety in patients taking kava extract. The reviewers noted kava appears to be safe and efficacious for short-term treatment.

Clinical trials support the reviewers findings. A study conducted at the Geriatric Hospital Elbroich in Dusseldorf, Germany, used a special kava extract (WS 1490 from Schwabe Pharmaceuticals in Karlsruhe, Germany) in 50 patients with non-psychotic anxiety.58 The treatment therapeutically reduced anxiety versus placebo, and was shown to be well tolerated and safe. Another trial using the WS 1490 extract found 200 mg/d for four weeks significantly improved sleep disturbances associated with non-psychotic anxiety disorders.59 And in a clinical, multicenter study, researchers provided 150 mg/d of WS 1490 to 141 adults suffering from neurotic anxiety.60 The researchers found consistent advantages for the kava extract over placebo in several psychiatric scales; however, the results were not as large as in trials using 300 mg/d. In addition, the researchers found the extract to be well tolerated with no influence on liver function tests.

Kavas possible effects on liver function have clouded the market for this botanical. A 2002 review from South Dakota State University noted kava has been shown to be an effective treatment for mild to moderate cases of anxiety.61 However, it noted between 1999 and 2002, there were several cases of liver toxicity supposedly associated with kava intake reported in Europe and the United States. While the reviewers note a causal relationship has not been definitively established, they suggest using kava with caution. A 2003 report in the Journal of Hepatology analyzed 29 cases of hepatitis linked to kava ingestion and found a complete recovery was noticed after withdrawal of kava, leading them to conclude kava use could lead to severe hepatotoxicity.62

A less polemical plant is valerian, a traditional herbal sleep remedy that is being studied for its impact on anxiety. Reviews note valerian has an excellent safety and tolerability profile, but data on its ability to treat anxiety are limited.63 One clinical study from the Universidade Federal do Parana, Brazil, investigated the effects of valerian extract, diazepam or placebo on subjects with generalized anxiety disorder.64 Both the herb and the drug significantly reduced the psychic anxiety factors, and researchers said their preliminary data suggests valerian may have a potential anxiolytic effect. While valerians method of action is not fully clear, a recent rat study suggests its effects are mediated through brain gamma-aminobutyric acid (GABA) receptors.65

Vinpocetinea derivative of the alkaloid vincamine, which is found in the aerial part of Vinca minor, a periwinkleis also thought to have application in mental wellness. It is commonly used to enhance cognitive function and memory, primarily because of its ability to enhance blood flow to the brain. Experiments have further suggested vinpocetines antioxidant properties may contribute to neuroprotective effects.

Beyond European and North American boundaries, several botanicals have been used in Asia for their ability to treat mental disorders. Chinese scullcap, Scutellaria baicalenis Georgi, has several active flavonoids with affinities for GABA receptors, active with sedative and anxiolytic effects.66,67 Further in vivo studies comparing a proprietary Chinese scullcap extract (as Calmatin from Burlington, Mass.-based Novia Nutraceuticals) to the pharmaceutical diazepam showed Calmatin relieved anxiety symptoms without a sedative effect.

Another Asian botanical used for emotional well-being is Apocynum venetum L. It has traditionally been used in Asia as a cardiotonic, anti-hypertensive, diuretic and antidepressant. Soft Gel Technologies has conducted studies on Apocynum venetum (as Venetron) for treatment of depression. Company studies show Venetron (which contains no less than 4 percent of the flavonoid glycosides isoquercitrin and hyperoside) shortened the immobility time in an animal model for antidepressant activity similar to that shown with IMI. Study investigators suggested the antidepressant effect may be related to the glycosides, which are also present in St. Johns wort.

As consumers increasingly search for natural ways to lift depression and subdue anxiety, manufacturers have an opportunity to provide scientifically-researched compounds for emotional wellness. While many nutrients, specialty compounds and botanicals have a long history of use, continued research investigations are likely to further the cause of these ingredients in helping consumers overcome mental disorders.

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