Chapter 13 Herbals and Dietary Supplements

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DOI: 10.1176/appi.books.9781585622825.240217

Manual of Clinical Psychopharmacology >

Chapter 13. Herbals and Dietary Supplements

INTRODUCTION

Herbal remedies and dietary supplements have become quite popular since the mid-1990s for the

treatment of psychiatric symptoms. Sales of St. John’s wort, omega-3 fatty acids, and DHEA

(dehydroepiandrosterone) have contributed to an estimated $6 billion in annual U.S. sales. As part

of a 1994 congressional act, an alternative medicine and dietary supplements office was created at

the National Institutes of Health to evaluate alternative agents. Herbal agents are, for the most

part, considered food supplements and are therefore not subject to U.S. Food and Drug

Administration (FDA) regulations. While it is illegal for a food supplement to claim to be efficacious

for a specific illness, there are few restrictions on a manufacturer’s claiming that a food supplement

helps with mood symptoms or gastrointestinal upset.

The lack of FDA regulation and oversight of compounds leads to a number of other differences

between pharmaceuticals and over-the-counter remedies. One important difference is that efficacy

does not need to be established in the case of a food supplement. In most cases, the data

supporting the use of many of these compounds are anecdotal and do not compare to those

required of prescription drugs. That is not to say that some herbals and supplements might not

help. It is only to underline that even herbal supplements as extensively studied as St. John’s wort

have been poorly studied compared with any prescription antidepressant.

Another important difference between herbals and prescription drugs is that the safety or optimal

dosing of a food supplement does not have to be established before the compound is marketed.

Prescription drugs are required to undergo extensive testing in animals to determine risks,

including those in pregnancy. Once the carcinogenic, mutagenic, pregnancy, and pharmacokinetic

toxicological profiles are established in animal testing, studies are then completed on healthy

volunteers. Only then are the first efficacy studies completed.

Herbals and food supplements are not typically subject to any safety testing at all.

Over-the-counter preparations, such as DHEA, clearly have hormonal properties and have had

important side effects in men and women. Yet, DHEA is still regarded as a food supplement and

thus not monitored or regulated.

Still another important difference is that the processing and manufacturing of herbals and dietary

supplements are far less consistent than the processing and manufacturing of prescription

medications. Herbals, for example, are not simple molecules. They are plant derivatives, and

different crops of the same plants grown in different parts of the country or world, processed by

different methods, may yield very different products. Thus, the pharmacological properties of one

batch of an herbal produced by the same manufacturer processed in a consistent way may be

different from those of the next batch. Some of these herbals are subject to rapid oxidation in room

air and thus lose their pharmacological properties quickly. In addition, the shelf life of most herbal

supplements is unknown, and there is evidence that many compounds are held in warehouses for

months before being distributed to retail outlets. The result is that some, perhaps many, herbals

are pharmacologically inert by the time they are consumed. Although many people may claim

benefits from using inert herbals, the placebo response rate for some psychiatric disorders is also

quite high.

Finally, some patients with serious illnesses such as depression or bipolar disorder may be tempted

to take over-the-counter preparations rather than to see a doctor. The general public often equates

“natural” with safe and good, while synthetic compounds are regarded with some suspicion. In

addition, herbals and dietary supplements are readily available at the health food store orPrint: Chapter 13. Herbals and Dietary Supplements http://www.psychiatryonline.com/popup.aspx?aID=240220&print=yes…

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supermarket. There is no need to see a psychiatrist to obtain a prescription for these dietary

supplements, and thus the stigma and cost associated with seeking psychiatric help are not a

factor. However, since many psychiatric disorders are potentially life-threatening, psychiatric

self-treatment would be analogous to patients with some forms of cancer treating themselves

rather than seeking medical assistance. Either example of self-treatment may have disastrous

consequences.

That being said, it is also likely that some herbals and dietary supplements will prove helpful for

some patients. After all, many effective compounds, from acetylsalicylic acid (aspirin) to digitalis,

were originally synthesized from plant products. It is important that these dietary compounds be

studied and refined. In this chapter, we review what is known about some of the more commonly

used herbal and dietary supplements (Table 13–1) and offer some suggestions for their role in the

treatment of psychiatric disorders.

Table 13–1. Commonly used herbal and dietary supplements and a hormonal preparation and their

role in treating psychiatric disorders

Supplement or preparation Uses Dosage Side effects/drug

interactions

Herbal

St. John’s wort (Hypericum perforatum) Depression,

anxiety

900–1,800

mg/day

GI distress, fatigue, rash,

CYP 3A3/4 enzyme inducer

kava (Piper methysticum) a

Anxiety 75–150 mg Intoxication, CNS

depression

valerian (Valeriana officinalis) Insomnia, anxiety — CNS depression, sedation

ginkgo (Ginkgo biloba) Memory loss,

sexual dysfunction

60–240

mg/day

Allergies, bleeds

Dietary

omega-3 fatty acids ( -linolenic acid,

eicosapentaenoic acid, docosahexaenoic

acid)

Bipolar disorder 9.6 g/day GI distress, fish odor

S-adenosylmethionine (SAMe) Depression 400–1,600

mg/day

Nausea

inositol

Depression 6–12 g/day GI distress, fish odor

Hormonal

DHEA (dehydroepiandrosterone) Depression 50–450

mg/day

Masculinization, hirsutism,

voice change

Note. CNS = central nervous system; CYP = cytochrome P450. GI = gastrointestinal.

aHas been associated with hepatotoxicity; should generally not be used at this time for any purpose.

1. JOHN’S WORT (HYPERICUM PERFORATUM)

St. John’s wort (Hypericum perforatum) has been employed for centuries in treating a variety of

ailments. The herb has been used in recent times primarily for a range of disorders from external

wound healing to the treatment of mild anxiety and depression. In medieval times, St. John’s wort

was often carried into battle in amulets worn around the neck to prevent evil from befalling a

soldier. Since mental illness was often attributed to demonic or witches’ spells, it is probable that

medieval peoples were using it for ailments such as depression and anxiety.

A mythology surrounds St. John’s wort. Known in biblical times as the Rose of Sharon, St. John’s

wort is said to have grown in the bloodied ground after the beheading of St. John the Baptist and

blossoms every June (around St. John’s Day). The plant is found on every continent exceptPrint: Chapter 13. Herbals and Dietary Supplements http://www.psychiatryonline.com/popup.aspx?aID=240220&print=yes…

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Antarctica. In the northwest United States, it grows wildly and is also referred to as Klamath weed,

since it grows extensively along the banks of the Klamath River, or goatweed, since goats tend to

feed on it. Sheepherders and goatherds are not fond of goatweed and often try to eradicate it, since

it may cause animals to develop hypersensitivity skin reactions.

In Germany, St. John’s wort is a popular first-line agent in the treatment of mild anxiety and

depression, with about 3 million prescriptions written in 1990. The herbal supplement is covered by

the National Health Service plan in Germany with a physician’s prescription similar to most

standard antidepressants. A majority of the studies done on St. John’s wort were performed in

Germany. However, patients who meet criteria for moderate or severe major depression tend to be

treated with standard antidepressants.

St. John’s wort became popular in the United States in the 1990s with the publication of a number

of lay manuscripts and books touting its benefits. In addition, St. John’s wort has been featured in

a number of nationally televised news programs. The Office of Alternative Medicine in the National

Institute of Mental Health called for studies and funded a major placebo-controlled study of more

than 300 patients that compared St. John’s wort with placebo and with sertraline. In that study,

sertraline (at a dosage of approximately 100 mg/day) and St. John’s wort did not separate from

placebo (Hypericum Depression Trial Study Group 2002). In another trial, St. John’s wort again was

not significantly more effective than placebo in 200 patients with major depression (Shelton et al.

2001). Fava et al. (2005) reported St. John’s wort to be significantly more effective than fluoxetine

but not than placebo. In contrast, a number of European trials have found the remedy to be

significantly more effective than placebo in patients with mild to moderate depression. For

example, Kasper and colleagues (2006) found an extract of St. Johns wort, WS 5570, superior to

placebo in the treatment of major depressive disorder. In addition, other work has suggested that

St. John’s wort may be effective in the prevention of relapse (Anghelescu et al. 2006).

Uses

Since St. John’s wort is a food supplement, it does not have an FDA-approved indication. However,

at least two manufacturers of St. John’s wort were pursuing an FDA indication for their particular

preparations to treat mild to moderate depression. At least 30 European studies support the use of

St. John’s wort in treating depression. Most, but not all, of these studies suggested that St. John’s

wort is more effective than placebo and may be as effective as comparison agents, usually tricyclic

antidepressants administered at low doses. The European studies have been criticized for a number

of methodological problems, including unclear entry criteria, inadequate dosing of comparison

agents, and lack of scientific rigor. As indicated above, a number of U.S. studies failed to

demonstrate efficacy.

St. John’s wort has also been preliminarily studied in the treatment of gastric distress and topically

in the treatment of first-degree burns and myalgias. These uses have been much less investigated

than has its utility in treating depression.

Mechanism of Action

Hypericum perforatum is not a simple molecule and contains many potentially active constituents.

It is unclear which, if any, of these components contribute to the effects of the herb. Standard

hypericin and hyperforan extracts of St. John’s wort have been shown to have mild serotonin

reuptake–blocking properties. There is little evidence that St. John’s wort produces any significant

inhibition of monoamine oxidase (MAO) in vitro, although such an effect is commonly attributed to

the herb. Hypericin also has affinity for sigma receptors, may inhibit COMT

(catechol-O-methyltransferase), and may enhance GABA ( -aminobutyric acid) receptors.

Side Effects and Drug Interactions

St. John’s wort is considered to be well tolerated. The most common side effects of St. John’s wort

are gastrointestinal upset, photodermatitis, and fatigue. In clinical trials, approximately 18% of

patients who took St. John’s wort reported side effects. This is considerably lower than the sidePrint: Chapter 13. Herbals and Dietary Supplements http://www.psychiatryonline.com/popup.aspx?aID=240220&print=yes…

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effects report with most standard antidepressant. Relatively few people stop St. John’s wort

because of side effects. There has been an isolated report of a reversible neuropathy associated

with a preparation of St. John’s wort, and an animal study that suggested reduced fertility. Like

prescription antidepressants, St. John’s wort has been associated with inducing mania or

hypomania in susceptible patients, but less commonly.

Serious drug interactions appear to be uncommon. There have been rare reports of a serotonin

syndrome associated with the use of selective serotonin reuptake inhibitors (SSRIs). Thus, many

clinicians advise against using the herb with an SSRI. Theoretically, St. John’s wort may enhance

the sedating effects of narcotics and benzodiazepines.

A more recent pharmacokinetic finding is that St. John’s wort is an inducer of the cytochrome P450

3A3/4 enzyme. This enzyme is responsible for metabolizing most drugs used in medical practice,

including calcium channel blockers, oral contraceptives, many antibiotics, and glucocorticoids. St.

John’s wort has been noted to enhance the metabolism of protease inhibitors in AIDS patients and

thus render these drugs less effective. St. John’s wort has been popular for treating depressive

symptoms in AIDS patients in some practices, and the addition of St. John’s wort to some AIDS

regimens may prove problematic.

Dosage and Administration

Determining the appropriate dosage of St. John’s wort presents some difficulty, since every

preparation—and perhaps every batch—of the herb is variable. The typical dose is 0.2–1 mg of the

hypericin or 900–1,800 mg/day of the whole herb taken in two or three divided doses. People also

take 1 g up to three times a day of the dried herb in a tea typically boiled in 150 mL of water and

then strained. People who use St. John’s wort typically start at 300–600 mg orally per day and then

increase the dosage every 1–2 weeks. As with prescription antidepressants, the effects may not be

seen for several weeks.

Our experience with St. John’s wort is that the effects appear to be modest but might not be

negligible in some patients. Given the results of the two controlled trials (i.e., Hypericum

Depression Trial Study Group 2002; Shelton et al. 2001), we are not advising patients to use it. If it

is to be used, we suggest stopping St. John’s wort for at least 3 days before starting an SSRI,

duloxetine, or venlafaxine.

OMEGA-3 FATTY ACIDS

Omega-3 fatty acids are building blocks of fats in the same way that amino acids are the building

blocks of proteins. They are found abundantly in coldwater fish, such as salmon and halibut, and

are also found in canola and soybean oil. The three most common forms of omega-3 fatty acids are

-linolenic acid, eicosapentaenoic acid, and docosahexaenoic acid. There has been a recent interest

in the role of omega-3 fatty acids in the treatment of bipolar disorder, depression, and

attention-deficit/hyperactivity disorder. In addition, diets deficient in omega-3 fatty acids have

been associated with increased rates of atherosclerotic disease.

Uses and Mechanism of Action

A number of reports over the past 10 years have suggested that affective illnesses may be

associated with deficiencies of some omega-3 fatty acids. For example, there appears to be some

correlation between a higher ratio of arachidonic acid to eicosapentaenoic acid in more severely

depressed patients than in less severely depressed patients. Other studies have suggested that

there may be lower levels of omega-3 fatty acids in the red blood cell membranes of depressed

patients than in healthy control subjects. Furthermore, there is some limited evidence that

omega-3 fatty acids may impact signal transduction in a manner analogous to lithium.

A preliminary double-blind study reported that adding supplemental omega-3 fatty acids to the

drug regimens of bipolar patients improved their outcomes (Stoll et al. 1999). In this study, 30

patients with bipolar disorder were randomized to receive either omega-3 supplements or olive oil

(as a control) for 4 months. They continued taking standard mood stabilizers. The omega-3–treatedPrint: Chapter 13. Herbals and Dietary Supplements http://www.psychiatryonline.com/popup.aspx?aID=240220&print=yes…

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patients experienced longer remission and more complete resolution of symptoms than did the

placebo-treated patients. However, more recent double-blind studies have failed to consistently

show a benefit in the treatment of bipolar disorder (see Chapter 5: “Mood Stabilizers”). Although

studies of omega fatty acids in patients with resistant unipolar depression have also been

inconsistent, some studies have suggested benefits of adding 1.0–4.4 g/day of eicosapentaenoic

acid to existing regimens.

Side Effects and Drug Interactions

The most common side effects are a tendency toward belching and gastrointestinal distress at

higher doses. In addition, patients may develop a fishlike odor to their breath. Some preparations

of omega-3 fatty acids may be more likely to cause this fish odor than are others.

There may be a tendency for omega-3 fatty acids at high doses to act as a blood thinner and reduce

clotting times. Thus, the combination of high doses of omega-3 fatty acids plus other blood

thinners, including aspirin or warfarin (Coumadin), may be problematic in some patients.

There are no known serious drug interactions between omega-3 fatty acids and mood stabilizers,

antidepressants, or antipsychotics.

Dosage and Administration

The dose of omega-3 fatty acids studied as an adjunctive treatment for bipolar disorder has been

9.6 g/day in divided doses. Capsule doses are usually 3,000 mg, so 1 capsule tid is probably

sufficient.

We have recommended this regimen in combination with standard mood stabilizers or

antidepressants to some patients because the risks of omega-3 fatty acids are small. In some

patients, this regimen appears to be helpful in treating their symptoms.

KAVA (PIPER METHYSTICUM)

Kava has been used for many years in folk medicine, and in Polynesia it is used as a ceremonial

beverage to induce relaxation. The kava plant is indigenous to the islands of the South Pacific and

belongs to the pepper family. In the past 2 years, kava has enjoyed significant popularity in the

United States as an over-the-counter treatment for “stress.”

Uses

People use kava for a variety of ailments, including anxiety and agitation. A small amount of data

suggests that when taken orally, in extracts that contain 70% kavapyrones, kava symptomatically

relieves nervous anxiety. There are anecdotal reports that kava may worsen depressive symptoms

in some patients with major depressive disorder.

Although kava is used in folk medicine as a topical treatment for skin diseases, for treating

urogenital complaints, and for treating respiratory ailments, there is no significant evidence that

kava helps any of these conditions.

Mechanism of Action

The mechanism of action of Piper methysticum, like that of other herbs, has not been fully

elucidated. There is some evidence that kava lactones act as GABA agonists in a manner similar to

benzodiazepines. However, the effect on GABA receptors is neither as potent nor as specific as it is

with benzodiazepines. In addition, kava may mildly block norepinephrine reuptake, but it has no

known effects on the serotonergic system.

Side Effects and Drug Interactions

In 2001, German physicians began to report a possible relationship between kava use and hepatic

damage. There were at least 30 known cases of hepatotoxicity in Switzerland and Germany, and in

some of these cases, the patients required liver transplants. In 2002, the herb was banned in

France, and both American and Canadian authorities, including the FDA, put out a warning thatPrint: Chapter 13. Herbals and Dietary Supplements http://www.psychiatryonline.com/popup.aspx?aID=240220&print=yes…

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kava has been associated with hepatic damage. In the United States, at least 60 cases of

hepatotoxicity, with at least 4 liver transplants, have been associated with kava use since 1998.

Therefore, kava should generally not be used at this time for any purpose.

Kava has also been associated with a number of other side effects, particularly when taken at high

doses for periods longer than 12 weeks. The most common side effects of kava are similar to those

of alcohol and benzodiazepines. These include sedation, ataxia, and motor incoordination. Kava

should not be used before driving or operating heavy machinery. Tolerance to increasing doses of

kava has been reported, but it is unclear whether withdrawal symptoms occur after prolonged use.

Extended use of high doses of kava has been associated with a pellagra-type illness with symptoms

such as dry flaky skin, reddened eyes, and a discoloration of the hair. Additionally, gastrointestinal

side effects and headaches have been reported with oral use of the herb.

Kava appears to potentiate the effects of other central nervous system (CNS) depressants,

including alcohol, benzodiazepines, and barbiturates. There are reports of confusion, delirium, and

temporary equilibrium problems associated with the combination of kava and alcohol.

Dosage and Administration

The oral dose of kava varies but typically ranges from 60 to 120 mg of kavapyrones extracted from

the kava root. A tea made from kava root is typically taken one to three times a day. Kava extracts

are often taken on an as-needed basis. Extended use of kava may be habit-forming.

Our experience is that kava may have some role in the treatment of anxiety states. However, kava

appears to have few advantages over benzodiazepines and is less potent than a benzodiazepine. It

appears to be able to induce intoxication, and long-term use, including the risk of dependence, has

not been evaluated adequately. We currently advise patients to avoid the use of kava, given its

risks and limited known benefits relative to prescribed anxiolytics.

VALERIAN (VALERIANA OFFICINALIS)

Like most herbs, valerian has been used throughout Europe, the United States, and Central America

for many years in folk medicine. The root of the valerian plant has been made into teas and liquid

solutions for a variety of ailments and is also used as a flavoring for some beverages and foods.

Uses

The primary uses for valerian have been in the symptomatic treatment of anxiety and insomnia.

Valerian has been shown to reduce sleep latency and possibly improve total sleep in some reports.

Its use as an adjunctive agent in depression has not been tested. In addition, people have used

valerian for headaches, intestinal pain, and dysmenorrhea, although there are no reliable data to

support these uses.

Mechanism of Action

A speculated mechanism by which valerian could impact anxiety and insomnia is through some

effect on GABA. Valerenic acid, derived from valerian root, appears to inhibit the breakdown of

GABA in the CNS and thus may facilitate GABAminergic neurotransmission. GABA is the most

prevalent inhibitory neurotransmitter in the CNS. Benzodiazepine hypnotics and anxiolytics work as

indirect agonists of GABA.

Side Effects and Drug Interactions

The primary side effects of valerian are sedation and drowsiness. Like other CNS depressants,

valerian can induce ataxia, motor incoordination, and dizziness, particularly at high doses.

Overdoses have been associated with abdominal cramping, tremor, ataxia, and confusion.

There is the potential for valerian to potentiate the effects of other CNS depressants, including

alcohol, benzodiazepines and barbiturates. Valerian has been reported to prolong thiopental and

pentobarbital effects.Print: Chapter 13. Herbals and Dietary Supplements http://www.psychiatryonline.com/popup.aspx?aID=240220&print=yes…

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Dosage and Administration

Extracts of 300–600 mg of valerian are usually taken one to three times per day orally or up to 2 g

in a tincture or a tea. Valerian is thought to have a low addictive potential, and some reports

suggest that the herb must be taken for a duration of 2–4 weeks to be maximally effective.

GINKGO (GINKGO BILOBA)

Ginkgo is an ancient folk remedy that has been used for hundreds and even thousands of years. The

ginkgo tree is found in Asia, and the leaves of the tree are processed to make tablets, capsules, or a

liquid solution.

Uses

Ginkgo is commonly used in the United States for memory problems associated with aging. Our

group participated in a study that found ginkgo biloba at a dosage of 120 mg/day to be significantly

more effective than placebo in retarding progression of dementia (Le Bars et al. 1997). The use of

ginkgo for depression has focused on reducing antidepressant-associated sexual dysfunction. The

evidence supporting the use of ginkgo for this purpose has been limited to case reports and an

open-label study of ginkgo in SSRI-induced sexual dysfunction.

Mechanism of Action

The ginkgolide derivatives of the leaf may increase cerebral and cardiovascular blood flow. It also

appears to be a harvester of free radicals. In addition, ginkgo has been shown to inhibit the activity

of platelet activating factor. Its mechanism in sexual dysfunction is speculated to result from

increased pudendal blood flow, but at the time of this writing there are no supporting data.

Side Effects and Drug Interactions

The whole leaf is associated with allergic reactions when taken orally or applied topically. In the

elderly, leaf extracts in high doses have been associated with confusion and with increased

susceptibility to bleeding.

Because ginkgo antagonizes platelet-activating factor, it increases the risk of bleeding with

antiplatelet drugs and warfarin. There is speculation that ginkgo can potentiate the effects of MAO

inhibitors.

Other, more mild side effects include headache, gastrointestinal upset, and rashes (Sommer and

Schatzberg 2002).

Dosage and Administration

For the treatment of sexual dysfunction, ginkgo is taken at a dosage of 120–240 mg/day. Case

reports suggest that ginkgo may need to be used daily for several weeks to treat

antidepressant-induced sexual side effects. For Alzheimer’s disease, the daily dosage is 180–360

mg/day (Sommer and Schatzberg 2002).

We have tried to use ginkgo to reverse SSRI-induced sexual dysfunction; in the patients studied,

we found that it works as poorly as most other recommended antidotes. However, since no

treatment works reliably in alleviating SSRI-induced sexual side effects, and since ginkgo may be

more benign than some antidotes, it may be worth trying. Sildenafil (Viagra) and bupropion appear

to be more effective than ginkgo, but there is an important placebo effect in sexual antidotes.

FOLATE AND B VITAMINS

Patients with major depression have been noted to have lower folate levels than healthy control

subjects (Fava et al. 1997), and folate is thought to play an important role in mood through its role

in the formation of S-adenosylmethionine (SAMe). In addition, patients with low folate levels have

poorer response to SSRIs (Papakostas et al. 2005). A number of studies have suggested that folate

may have a role in the adjunctive treatment of depression. For example, Coppen and colleagues

(Abou-Saleh and Coppen 2006; Coppen and Bailey 2000; Coppen and Bolander-Gouaille 2005) Print: Chapter 13. Herbals and Dietary Supplements http://www.psychiatryonline.com/popup.aspx?aID=240220&print=yes…

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found that women who were treated with 500 g of folic acid along with fluoxetine were more

likely to respond than those receiving placebo along with fluoxetine. Similarly, Alpert and

colleagues (2002) found that the addition of folinic acid (leucovorin) improved response, albeit

modestly, in a group of patients who had not achieved an adequate response to an SSRI alone.

Low B12 serum levels have also been associated with poorer outcome in depressed patients

(Hintikka et al. 2003). Both folate and B12 are major determinants of the one-carbon metabolism in

which SAMe is formed. While it has been understood for many years that B12 deficiency in the form

of pernicious anemia can have many severe neuropsychiatric sequelae, including dementia and

psychosis, it has only more recently been appreciated that milder forms of B12 deficiency may be

associated with depressive symptoms. Likewise, a B6 deficiency has also been associated with

depressive symptoms.

Recommending a healthy, well-balanced diet is more useful than routinely recommending vitamin

supplements. However, it is worthwhile to check B12 levels and perhaps folate levels in geriatric

depressed patients, patients who have undergone gastric resection or bypass, alcoholic patients,

and cachectic depressed patients. Given the low risks of folate and B12, it may also be reasonable

to treat some patients empirically, especially those at risk for vitamin deficiency. Normally, folate is

well tolerated as a supplement. The typical oral dosage of folate is 500 g/day. Dosages higher

than 1,000 g/day may interfere with B12 levels and may be associated with inducing a B12

deficiency. Folate at very high dosages (>15,000 g/day) have also been associated with nausea,

skin reactions, and seizures. In addition, high doses of folate may interfere with the absorption of

anticonvulsants, barbiturates, and estrogen. For severe B12 deficiency, supplements are given

intramuscularly at doses of 1 mg one to four times per week. Typical oral doses of B12 are

1,000–2,000 g/day. While B12 overdoses are extremely uncommon in healthy people, symptoms

of excessive B12 intake may include pruritis, burning sensations, and other tactile responses. The

optimal dose of both folate and B12 in depressed patients has not been established.

S-ADENOSYLMETHIONINE (SAME)

S-Adenosylmethionine is still among the most popular over-the-counter treatment for depressive

symptoms after St. John’s wort. Several books have been devoted to the subject of SAMe in

treating depression, and some health food stores have trouble keeping it in stock. SAMe has been

used, both orally and intravenously, in treating major depression and, as anecdotally reported, has

been used to augment standard antidepressants.

Uses

Like many over-the-counter preparations, SAMe is used in treating many ailments. It has been less

well studied in major depression than has St. John’s wort. One meta-analysis suggested that SAMe

is about 17%–38% more effective than placebo, which would make it comparable to the average

antidepressant. However, randomized, head-to-head comparisons of SAMe and a standard

antidepressant are lacking. Thus, it is not possible to accurately determine how SAMe compares

with antidepressants in the same pertinent population. There have been some reports that the

addition of 200 mg of SAMe to a standard dose of imipramine resulted in faster response compared

with placebo. The studies of SAMe typically involved mild to moderate depression. A recent

meta-analysis also concluded that there may be a role for SAMe in the treatment of depression

(Williams et al. 2005).

Another studied use of SAMe is in the treatment of osteoarthritis. There have been preliminary

studies of the use of SAMe in treating fibromyalgia and AIDS-related myelopathy.

Mechanism of Action

SAMe is involved in a variety of transmethylation reactions, including those involved in the

synthesis and activation of monoamine neurotransmitters. Thus, it can potentially increase the

activity and availability of serotonin, norepinephrine, and dopamine. There are limited data

suggesting that SAMe may also block the reuptake of monoamines. SAMe does appear to cross thePrint: Chapter 13. Herbals and Dietary Supplements http://www.psychiatryonline.com/popup.aspx?aID=240220&print=yes…

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blood-brain barrier, but it has a short half-life (1.5 hours).

Side Effects and Drug Interactions

SAMe appears to be well tolerated in most people. The most common side effect is nausea, which is

associated with increasing the dose of SAMe. There have been a few reports of SAMe’s increasing

anxiety in some depressed patients and also inducing hypomania in susceptible patients.

There are no known drug interactions for SAMe.

Dosage and Administration

The typical starting dosage of SAMe is 400–800 mg/day, with the dosage increasing to a maximum

of 1,600 mg/day. Since SAMe has a short half-life, the compound should be dosed two to three

times per day. It appears to take 2–4 weeks before benefits can be assessed. Intravenous and

intramuscular injections of SAMe have typically involved doses of 200–400 mg. It is unclear

whether the injection of SAMe has significant clinical advantages over the parenteral form of the

compound, but the intravenous form increases the bioavailability of the compound, since SAMe

undergoes a significant first-pass effect.

We have recommended SAMe to the occasional patient who is getting an inadequate response to

one antidepressant and who prefers not to add a standard augmenting agent, such as lithium, or

another antidepressant to the original agent. SAMe is more expensive than a generic

antidepressant, and its utility is questionable.

INOSITOL

Inositol has been used for many years and has been reported to be of benefit for some psychiatric

disorders, including depression and panic. Inositol appears to be effective in some animal models

of depression. Clinical experience with inositol as an antidepressant has been limited, but,

anecdotally, it has not been helpful to some patients.

Uses

The use of inositol in treating major depression has been limited to a few small studies. One study

compared 12 g of inositol with placebo in 28 patients with major depression for 4 weeks and found

that inositol was superior. Another, more recent study of inositol added to an SSRI found no

difference from an SSRI or placebo in efficacy or in speed of onset. Nierenberg and colleagues

(2006) compared the addition of inositol, lamotrigine, or risperidone to an established mood

stabilizer for patients with resistant bipolar depression. There were no differences on primary

outcome measures among the three augmenting treatments, but lamotrigine appeared superior on

some secondary outcomes. It is not possible to say from this study design whether inositol is as

effective as standard treatments or whether inositol is simply as ineffective as other augmenting

strategies.

Mechanism of Action

The mechanism of action of inositol as a potential adjunctive treatment of depression is largely

unknown. There is evidence that inositol can reverse desensitization of serotonin receptors and

may affect other monoamines.

Side Effects and Drug Interactions

Side effects of inositol appear to be very limited. Doses up to 18 g/day have not been associated

with consistent side effects. Some patients complain of gastrointestinal distress with higher doses.

Inositol/lecithin combinations have been associated with a fish-type odor.

Dosage and Administration

The doseage of inositol used in the treatment is typically 12 g/day taken orally in a powder form or

in tablets.Print: Chapter 13. Herbals and Dietary Supplements http://www.psychiatryonline.com/popup.aspx?aID=240220&print=yes…

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It appears unlikely that inositol is effective as an adjunctive agent. However, inositol might be

worth considering early in the algorithm in some depressed patients as an augmenting agent. Our

limited experience with inositol indicates that it is as benign as it is ineffective.

DHEA (DEHYDROEPIANDROSTERONE)

DHEA has gained popularity in recent years as an over-the-counter hormonal preparation that is

said to reverse problems associated with aging, including sexual dysfunction, muscle wasting,

fatigue, and memory difficulties. There is limited evidence that DHEA has any of these benefits, but

a growing body of data has indicated that DHEA may be problematic in some patients.

Uses

DHEA has been studied in major depression. One study (Wolkowitz et al. 1999) found that 90

mg/day of DHEA for 6 weeks resulted in significant improvement in the condition of 5 out of 11

patients, whereas placebo did not lead to a response in any of the patients. Another study found

that DHEA at a dosage of 90 mg/day for 3 weeks and 450 mg/day for another 3 weeks helped

alleviate depression better than placebo in 46 patients with midlife-onset major or minor

depression (Schmidt et al. 2005). Likewise, Rabkin et al. (2006) found that DHEA at 100–400

mg/day was superior to placebo in treating depressive symptoms in HIV patients.

Mechanism of Action

DHEA is metabolized into androstenedione, which is then converted to both androgens and

estrogens. Thus, it can increase the levels of both estrogens and androgens in men and women.

Side Effects and Drug Interactions

Reported side effects include hirsutism and voice deepening in women, hair loss and an increased

risk for prostate cancer in men, and liver dysfunction in both sexes.

DHEA may potentiate or antagonize other sex steroids.

Dosage and Administration

The dosage of DHEA reported to help depression ranges from 50 to 450 mg/day.

At this time we are advising against the use of DHEA either alone or in combination with

antidepressants. The limited efficacy data on DHEA do not suggest greater efficacy than standard

antidepressants. In addition, the long-term risks associated with DHEA are also unknown but may

be considerable in some patients.

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