Herbal and Dietary Supplements for Treatment of Anxiety Disorders

Am Fam Physician. 2007 Aug 15;76(4):549-556.

Use of complementary and alternative medicine has increased over the past decade. A variety of studies have suggested that this use is greater in persons with symptoms or diagnoses of anxiety and depression. Data support the effectiveness of some popular herbal remedies and dietary supplements; in some of these products, particularly kava, the potential for benefit seems greater than that for harm with short-term use in patients with mild to moderate anxiety. Inositol has been found to have modest effects in patients with panic disorder or obsessive-compulsive disorder. Physicians should not encourage the use of St. John's wort, valerian, Sympathyl, or passionflower for the treatment of anxiety based on small or inconsistent effects in small studies. Although the evidence varies depending on the supplement and the anxiety disorder, physicians can collaborate with patients in developing dietary supplement strategies that minimize risks and maximize benefits.

Use of complementary and alternative medicine in all of its varieties, such as herbal remedies and dietary supplements, increased from 34 percent of the overall U.S. population in 1990 to 42 percent in 1997.1 Use appears to be twice as great in persons reporting anxiety and depression than in those reporting any other problem, except for back and neck pain.1 Based on results of two large-scale community surveys,2,3 investigators have noted an association between both panic disorder and major depression and the use of complementary and alternative medicine.

SORT: KEY RECOMMENDATIONS FOR PRACTICE

Clinical recommendation Evidence rating References Comments

Short-term use of kava is recommended for patients with mild to moderate anxiety disorders who are not using alcohol or taking other medicines metabolized by the liver, but who wish to use “natural” remedies.

A

4, 5

Cochrane systematic review of seven RCTs (n = 380), with findings supported by five lower-quality trials (n = 320); side effects were rare and mild; same results with only extract WS1490 trials

Use of inositol in a dosage of 12 to 18 g per day is a treatment option for panic disorder.

B

24, 25

Effectiveness similar to SSRI and better than placebo for reducing intensity and frequency of panic attacks; side-effect profile comparable to SSRI; supported by two RCTs, although both were small

Inositol, 12 to 18 g per day, may be used to treat obsessive-compulsive disorder but not in combination with SSRIs.

B

26, 27

In trials of patients with treatment-resistant OCD, inositol by itself was better than placebo in reducing OCD symptoms26 but not in reducing anxiety scale scores; when added to SSRIs, inositol had no additional effect27

Physicians should not encourage the use of St. John's wort, valerian, Sympathyl, or passionflower for anxiety based on small or inconsistent effects in small studies. Side-effect profiles are benign.

B

1623

Small, unreplicated trials with design flaws suggest some limited effectiveness

All other nutritional supplements have no research evidence suggesting a positive effect on anxiety disorders. Physicians should recommend other treatments.

C

No evidence beyond testimonials, effects on nonclinical groups, or hypothetical mechanisms of action


RCT = randomized controlled trial; SSRI = selective serotonin reuptake inhibitor; OCD = obsessive-compulsive disorder.

A = consistent, good-quality patient-oriented evidence; B = inconsistent or limited-quality patient-oriented evidence; C = consensus, disease-oriented evidence, usual practice, expert opinion, or case series. For information about the SORT evidence rating system, see page 483 or http://www.aafp.org/afpsort.xml.

SORT: KEY RECOMMENDATIONS FOR PRACTICE

View Table

SORT: KEY RECOMMENDATIONS FOR PRACTICE

Clinical recommendation Evidence rating References Comments

Short-term use of kava is recommended for patients with mild to moderate anxiety disorders who are not using alcohol or taking other medicines metabolized by the liver, but who wish to use “natural” remedies.

A

4, 5

Cochrane systematic review of seven RCTs (n = 380), with findings supported by five lower-quality trials (n = 320); side effects were rare and mild; same results with only extract WS1490 trials

Use of inositol in a dosage of 12 to 18 g per day is a treatment option for panic disorder.

B

24, 25

Effectiveness similar to SSRI and better than placebo for reducing intensity and frequency of panic attacks; side-effect profile comparable to SSRI; supported by two RCTs, although both were small

Inositol, 12 to 18 g per day, may be used to treat obsessive-compulsive disorder but not in combination with SSRIs.

B

26, 27

In trials of patients with treatment-resistant OCD, inositol by itself was better than placebo in reducing OCD symptoms26 but not in reducing anxiety scale scores; when added to SSRIs, inositol had no additional effect27

Physicians should not encourage the use of St. John's wort, valerian, Sympathyl, or passionflower for anxiety based on small or inconsistent effects in small studies. Side-effect profiles are benign.

B

1623

Small, unreplicated trials with design flaws suggest some limited effectiveness

All other nutritional supplements have no research evidence suggesting a positive effect on anxiety disorders. Physicians should recommend other treatments.

C

No evidence beyond testimonials, effects on nonclinical groups, or hypothetical mechanisms of action


RCT = randomized controlled trial; SSRI = selective serotonin reuptake inhibitor; OCD = obsessive-compulsive disorder.

A = consistent, good-quality patient-oriented evidence; B = inconsistent or limited-quality patient-oriented evidence; C = consensus, disease-oriented evidence, usual practice, expert opinion, or case series. For information about the SORT evidence rating system, see page 483 or http://www.aafp.org/afpsort.xml.

Currently, the preferred treatment for anxiety disorders is cognitive behavior therapy and pharmacologic agents. Beta blockers or benzodiazepines are used for time-limited and predictable anxiety disorders, whereas selective serotonin reuptake inhibitors (SSRIs), selective serotonin-norepinephrine reuptake inhibitors, tricyclic antidepressants, buspirone (Buspar), or monoamine oxidase inhibitors are preferred for chronic or recurrent anxiety disorders.

In recent years, studies using herbal remedies and supplements to treat mild to moderate anxiety disorders have emerged. It is important for physicians to recognize that supplements offer both benefits and risks. By doing so, they can avoid an overly dismissive attitude that discourages patients from disclosing their supplement use. At the same time, understanding the limits of available evidence allows physicians to collaborate with interested patients in developing dietary supplement strategies that minimize risks and maximize benefits.

In this article, the supplements purported to ameliorate anxiety disorders are divided into three groups: herbal supplements, nutritional supplements, and neurotransmitter and hormonal precursors. These divisions are somewhat arbitrary in that all of the products are taken orally, are available over the counter, are marketed with a variety of health claims on the Internet, and are justified by their purported ultimate effects on the neurotransmitter systems that mediate worry, stress, or fatigue symptoms in patients with anxiety disorders.

Information on supplements that claim to be useful or commonly used for anxiety disorders was obtained from several Internet sites, particularly http://www.revolutionhealth.com/drugs-treatments, http://www.healthyplace.com/Communities/Anxiety/treatment/alternative_treatment.asp, and http://www.naturaldatabase.com. Medline via Ovid was used to search for clinical trials, guidelines, and meta-analyses that tested or asserted the effectiveness of these preparations in the treatment of patients with diagnosed anxiety disorders. Table 1 includes suggested supplements that have some evidence of effectiveness for treating anxiety. Only therapies with evidence of effectiveness are discussed in this review.

Table 1

Supplements with Clinical Trial Evidence of Effectiveness or Noneffectiveness for Treating Anxiety

Type of evidence Herbal supplements Nutritional supplements Neurotransmitter/hormonal precursors

Effectiveness based on meta-analysis or multiple RCTs

Kava

Effectiveness based on a single double-blind, placebo-controlled RCT

St. John's wort (for somatoform disorders), sympathyl (California poppy, hawthorn, elemental magnesium)

Inositol, 18 g (one RCT for panic disorder and one RCT for OCD)

5-hydroxytryptophan (serotonin precursor; for panic disorder)

Weak effectiveness based on clinical/open trials

Passionflower, St. John's wort (for GAD), valerian

Clinical trials demonstrating noneffectiveness

Cannabis

Omega-3 fatty acids (as adjunct for treatment-resistant OCD)


note: The preparations are listed in order from the most evidence of effectiveness to the least evidence.

RCT = randomized controlled trial; OCD = obsessive-compulsive disorder; GAD = generalized anxiety disorder.

Table 1   Supplements with Clinical Trial Evidence of Effectiveness or Noneffectiveness for Treating Anxiety

View Table

Table 1

Supplements with Clinical Trial Evidence of Effectiveness or Noneffectiveness for Treating Anxiety

Type of evidence Herbal supplements Nutritional supplements Neurotransmitter/hormonal precursors

Effectiveness based on meta-analysis or multiple RCTs

Kava

Effectiveness based on a single double-blind, placebo-controlled RCT

St. John's wort (for somatoform disorders), sympathyl (California poppy, hawthorn, elemental magnesium)

Inositol, 18 g (one RCT for panic disorder and one RCT for OCD)

5-hydroxytryptophan (serotonin precursor; for panic disorder)

Weak effectiveness based on clinical/open trials

Passionflower, St. John's wort (for GAD), valerian

Clinical trials demonstrating noneffectiveness

Cannabis

Omega-3 fatty acids (as adjunct for treatment-resistant OCD)


note: The preparations are listed in order from the most evidence of effectiveness to the least evidence.

RCT = randomized controlled trial; OCD = obsessive-compulsive disorder; GAD = generalized anxiety disorder.

Patients often justify the use of certain preparations on the basis of irrelevant or misleading evidence; to help physicians recognize such preparations, those supplements with no clinical evidence of effectiveness in reducing anxiety are presented in Table 2. Clearly, the vast majority of supplements with purported anxiolytic effects have no evidence of clinical benefit.

Table 2

Supplements with No Clinical Trial Evidence of Effectiveness in Anxiety Disorders

Herbal supplements

Ashwagandha (Withania somnifera); Bach flower essences; bacopa; berocca; borage juice (starflower); bugleweed (Lycopus virginicus); catnip; chamomile; damiana; fennel; feverfew; ginkgo; ginseng; golden root (Rhodiola rosea); gotu kola; hops; kanna; lemon balm; lemongrass leaves; licorice; meadowsweet; motherwort; mullein (Verbascum sinuatum); mulungu; noni (Morinda citrifolia); peppermint; pine bark extract; reishi (Ganoderma lucidum); Relora (magnolia/phellodendron); schisandra; scullcup (skullcap); verbena (blue vervain)

Nutritional supplements

Adrenal extracts; carbohydrate-rich diet; garum armoricum (great bluefish); ginger; l-theanine (green tea); macrobiotic diet; milk peptides (New life Tryptozen); oats; perilla oil (perilla frutescens); vitamins B3, B6, B12, and C

Neurotransmitter and hormonal precursors

Amino acids (l-phenylalanine/phenylalanine [norepinephrine precursor], l -arginine, l-lysine, l-glutamine, l-leucine); melatonin; pregnenolone;phytoestrogens (soy or Mexican yam); tyrosine (norepinephrine precursor); SAMe (S-adenosyl-l-methionine)

Table 2   Supplements with No Clinical Trial Evidence of Effectiveness in Anxiety Disorders

View Table

Table 2

Supplements with No Clinical Trial Evidence of Effectiveness in Anxiety Disorders

Herbal supplements

Ashwagandha (Withania somnifera); Bach flower essences; bacopa; berocca; borage juice (starflower); bugleweed (Lycopus virginicus); catnip; chamomile; damiana; fennel; feverfew; ginkgo; ginseng; golden root (Rhodiola rosea); gotu kola; hops; kanna; lemon balm; lemongrass leaves; licorice; meadowsweet; motherwort; mullein (Verbascum sinuatum); mulungu; noni (Morinda citrifolia); peppermint; pine bark extract; reishi (Ganoderma lucidum); Relora (magnolia/phellodendron); schisandra; scullcup (skullcap); verbena (blue vervain)

Nutritional supplements

Adrenal extracts; carbohydrate-rich diet; garum armoricum (great bluefish); ginger; l-theanine (green tea); macrobiotic diet; milk peptides (New life Tryptozen); oats; perilla oil (perilla frutescens); vitamins B3, B6, B12, and C

Neurotransmitter and hormonal precursors

Amino acids (l-phenylalanine/phenylalanine [norepinephrine precursor], l -arginine, l-lysine, l-glutamine, l-leucine); melatonin; pregnenolone;phytoestrogens (soy or Mexican yam); tyrosine (norepinephrine precursor); SAMe (S-adenosyl-l-methionine)

Herbal Supplements

KAVA

There is substantial evidence that kava has a positive effect on the symptoms of anxiety disorders. Table 3 summarizes the evidence on the effectiveness and safety of kava in patients with anxiety disorders.412

Table 3

Evidence Regarding the Effectiveness and Safety of Kava in Anxiety Disorders

Design Description Comments

Meta-analyses on GAD

A Cochrane systematic review identified 12 RCTs of effects of kava on patients with GAD4; the meta-analysis included seven trials that met quality criteria (n = 380); kava significantly reduced Hamilton Anxiety Scale scores, although the weighted mean difference between kava and placebo was only 3.9 scale points; the other five trials (n = 320) showed similar tendencies; a replication meta-analysis involving only those RCTs that used extract WS1490 replicated and extended these results5

Kava was consistently better than placebo in producing small reductions in anxiety symptoms; side effects noticed across all studies were “mild, transient, and infrequent”4; the authors concluded that kava taken for one to 24 weeks was safe and mildly effective; the replication5 allowed more comparisons between patient subgroups and suggested most improvement effects in women and patients younger than 53 years

RCTs on GAD

Recent small RCTs involving patients with GAD (n = 64) showed no significant effect of kava,6 with treatments typically lasting four weeks

Trial durations were short, and sample size was small; although studies of eight weeks' duration7 have shown effectiveness, a 25-week study8 showed that therapeutic effects started in the eighth week

RCT on safety

Recent examinations of adverse event reports with kava9 and improved understanding of the pharmacologic substances in kava10 show that its safety compares favorably with FDA-approved treatments for anxiety disorders

Researchers concluded that liver toxicity is rare and idiosyncratic, with the majority of reported cases resulting from the combination of kava with other hepatoactive agents; the benefits of kava seem to outweigh its risks10

Case reports on safety

Cases of liver toxicity have been reported, some requiring organ transplants; kava preparations withdrawn from the market in many countries; the FDA issued an advisory11; later, research suggested that nonstandard inclusion of the kava plant's bark in kava preparations increased toxicity level12

Unclear if dosing, preexisting liver damage, or toxic combinations with other hepatoactive agents were causative


GAD = generalized anxiety disorder; RCT = randomized controlled trial; FDA = U.S. Food and Drug Administration.

Information from references 4 through 12.

Table 3   Evidence Regarding the Effectiveness and Safety of Kava in Anxiety Disorders

View Table

Table 3

Evidence Regarding the Effectiveness and Safety of Kava in Anxiety Disorders

Design Description Comments

Meta-analyses on GAD

A Cochrane systematic review identified 12 RCTs of effects of kava on patients with GAD4; the meta-analysis included seven trials that met quality criteria (n = 380); kava significantly reduced Hamilton Anxiety Scale scores, although the weighted mean difference between kava and placebo was only 3.9 scale points; the other five trials (n = 320) showed similar tendencies; a replication meta-analysis involving only those RCTs that used extract WS1490 replicated and extended these results5

Kava was consistently better than placebo in producing small reductions in anxiety symptoms; side effects noticed across all studies were “mild, transient, and infrequent”4; the authors concluded that kava taken for one to 24 weeks was safe and mildly effective; the replication5 allowed more comparisons between patient subgroups and suggested most improvement effects in women and patients younger than 53 years

RCTs on GAD

Recent small RCTs involving patients with GAD (n = 64) showed no significant effect of kava,6 with treatments typically lasting four weeks

Trial durations were short, and sample size was small; although studies of eight weeks' duration7 have shown effectiveness, a 25-week study8 showed that therapeutic effects started in the eighth week

RCT on safety

Recent examinations of adverse event reports with kava9 and improved understanding of the pharmacologic substances in kava10 show that its safety compares favorably with FDA-approved treatments for anxiety disorders

Researchers concluded that liver toxicity is rare and idiosyncratic, with the majority of reported cases resulting from the combination of kava with other hepatoactive agents; the benefits of kava seem to outweigh its risks10

Case reports on safety

Cases of liver toxicity have been reported, some requiring organ transplants; kava preparations withdrawn from the market in many countries; the FDA issued an advisory11; later, research suggested that nonstandard inclusion of the kava plant's bark in kava preparations increased toxicity level12

Unclear if dosing, preexisting liver damage, or toxic combinations with other hepatoactive agents were causative


GAD = generalized anxiety disorder; RCT = randomized controlled trial; FDA = U.S. Food and Drug Administration.

Information from references 4 through 12.

Kava dramatically inhibits the cytochrome P450 enzyme used by the liver to metabolize many medications, potentially altering the potency of these other medications.13,14 Thus, it is important to be aware of the risk of drug interactions with kava. Other side effects reported with long-term use include a reversible skin rash or lesion and a yellow tint to the skin, but these reports have not been routine. Despite the absence of long-term data on safety and effectiveness,4,13,15 the evidence shows that short-term use (i.e., up to 24 weeks) can lead to small improvements in generalized anxiety,4 and that short-term risks do not outweigh the benefits.

For patients with mild to moderate anxiety who wish to use “natural” remedies and are not using alcohol or taking other medications that are metabolized by the liver, kava appears to be acceptable for short-term use.

ST. JOHN'S WORT

St. John's wort is a popular supplement for treating depression but is much less popular for treating anxiety disorders. Studies specifically testing the effects of St. John's wort on patients with anxiety are extremely limited. Table 4 summarizes the evidence for the effectiveness and safety of St. John's wort in the treatment of anxiety disorders.1623

Table 4

Evidence Regarding the Effectiveness and Safety of St. John's Wort, Valerian, Sympathyl, and Passionflower in Anxiety Disorders

Design Description Comments

RCT with St. John's wort in OCD

Compared 30 patients with OCD taking LI 160 extract (range: 300 to 1,800 mg) and 30 patients with OCD taking placebo for 12 weeks16; St. John's wort had no effect on reducing Yale-Brown Obsessive-Compulsive Scale total or subscale scores

Agitation side effect more common with St. John's wort

Open, uncontrolled study of St. John's wort in OCD

Significant reductions in the Yale-Brown Obsessive-Compulsive Scale score in 12 patients with OCD starting one week into the study and continuing throughout the 12-week trial17; the compound used was a 450-mg, extended-release formulation of 0.3% Hypericum taken two times a week

The small number of patients and lack of comparison to placebo make this evidence weak; few side effects reported

RCT with St. John's wort in social phobias

Compared flexible doses of LI 160 extract (range: 300 to 1,800 mg twice a day) and placebo in 40 patients with social phobias18; St. John's wort had no effect in reducing anxiety scores

Side effects no worse than placebo

RCT with St. John's wort in somatoform disorders

St. John's wort was used to treat somatoform disorders using reductions in the Hamilton Anxiety Scale somatic anxiety subscale score as the primary outcome measure19; after patients with significant depressive symptoms were excluded, 150 patients were randomized to St. John's wort or placebo; dosage of the LI 160 extract was 300 mg twice a day

Somatoform disorders have complex relationship with anxiety disorders

Results showed a strong positive effect of St. John's wort, compared with placebo, in reducing somatic anxiety, psychic anxiety, overall anxiety scores, and physician and patient ratings of somatoform disorder symptoms

Open trial with St. John's wort plus valerian in anxiety and depression

Valerian was used in combination with St. John's wort to treat patients with comorbid anxiety and depression; the combination was better than St. John's wort alone at reducing anxiety scores20

Suggestive improvement of St. John's wort with addition of valerian; very few side effects

RCT with valerian versus diazepam (Valium) and placebo in GAD

Randomized, double-blind, placebo-controlled comparison of valerian with diazepam in GAD, 12 patients per group for four weeks21; no differences between valerian and placebo, or between diazepam and placebo

Too underpowered to demonstrate differences in effectiveness; no differences in side effects

RCT with Sympathyl versus placebo; two tablets twice a day in GAD

Double-blind randomized trial conducted among patients with mild to moderate GAD in 22 general practices in Paris, France22; Sympathyl (n = 130) and placebo (n = 134) groups were relatively large; after three months the Sympathyl group showed a 10.6-point decline in the Hamilton Anxiety Scale score, whereas the placebo group showed an 8.9-point decline

Statistically significant advantage for Sympathyl compared with placebo, but size of difference (1.7 scale points) very small

RCT of passionflower versus oxazepam (Serax; brand no longer available in the United States) in GAD

Each group had 18 patients with GAD23; both groups started with mean Hamilton Anxiety Scale scores of 20 and ended with significant reductions to 6; the groups also had the same level of side effects

Both groups equally positive but small study with no placebo group; results unclear


RCT = randomized controlled trial; OCD = obsessive-compulsive disorder; GAD = generalized anxiety disorder.

Information from references 16 through 23.

Table 4   Evidence Regarding the Effectiveness and Safety of St. John's Wort, Valerian, Sympathyl, and Passionflower in Anxiety Disorders

View Table

Table 4

Evidence Regarding the Effectiveness and Safety of St. John's Wort, Valerian, Sympathyl, and Passionflower in Anxiety Disorders

Design Description Comments

RCT with St. John's wort in OCD

Compared 30 patients with OCD taking LI 160 extract (range: 300 to 1,800 mg) and 30 patients with OCD taking placebo for 12 weeks16; St. John's wort had no effect on reducing Yale-Brown Obsessive-Compulsive Scale total or subscale scores

Agitation side effect more common with St. John's wort

Open, uncontrolled study of St. John's wort in OCD

Significant reductions in the Yale-Brown Obsessive-Compulsive Scale score in 12 patients with OCD starting one week into the study and continuing throughout the 12-week trial17; the compound used was a 450-mg, extended-release formulation of 0.3% Hypericum taken two times a week

The small number of patients and lack of comparison to placebo make this evidence weak; few side effects reported

RCT with St. John's wort in social phobias

Compared flexible doses of LI 160 extract (range: 300 to 1,800 mg twice a day) and placebo in 40 patients with social phobias18; St. John's wort had no effect in reducing anxiety scores

Side effects no worse than placebo

RCT with St. John's wort in somatoform disorders

St. John's wort was used to treat somatoform disorders using reductions in the Hamilton Anxiety Scale somatic anxiety subscale score as the primary outcome measure19; after patients with significant depressive symptoms were excluded, 150 patients were randomized to St. John's wort or placebo; dosage of the LI 160 extract was 300 mg twice a day

Somatoform disorders have complex relationship with anxiety disorders

Results showed a strong positive effect of St. John's wort, compared with placebo, in reducing somatic anxiety, psychic anxiety, overall anxiety scores, and physician and patient ratings of somatoform disorder symptoms

Open trial with St. John's wort plus valerian in anxiety and depression

Valerian was used in combination with St. John's wort to treat patients with comorbid anxiety and depression; the combination was better than St. John's wort alone at reducing anxiety scores20

Suggestive improvement of St. John's wort with addition of valerian; very few side effects

RCT with valerian versus diazepam (Valium) and placebo in GAD

Randomized, double-blind, placebo-controlled comparison of valerian with diazepam in GAD, 12 patients per group for four weeks21; no differences between valerian and placebo, or between diazepam and placebo

Too underpowered to demonstrate differences in effectiveness; no differences in side effects

RCT with Sympathyl versus placebo; two tablets twice a day in GAD

Double-blind randomized trial conducted among patients with mild to moderate GAD in 22 general practices in Paris, France22; Sympathyl (n = 130) and placebo (n = 134) groups were relatively large; after three months the Sympathyl group showed a 10.6-point decline in the Hamilton Anxiety Scale score, whereas the placebo group showed an 8.9-point decline

Statistically significant advantage for Sympathyl compared with placebo, but size of difference (1.7 scale points) very small

RCT of passionflower versus oxazepam (Serax; brand no longer available in the United States) in GAD

Each group had 18 patients with GAD23; both groups started with mean Hamilton Anxiety Scale scores of 20 and ended with significant reductions to 6; the groups also had the same level of side effects

Both groups equally positive but small study with no placebo group; results unclear


RCT = randomized controlled trial; OCD = obsessive-compulsive disorder; GAD = generalized anxiety disorder.

Information from references 16 through 23.

The evidence of positive effects of St. John's wort on anxiety disorders is weak. No placebo-controlled, randomized, double-blind trials have shown St. John's wort to be effective in treating generalized anxiety disorder, post-traumatic stress disorder, obsessive-compulsive disorder (OCD), or phobias. The only effective trial involved patients with somatoform disorder, although the relationship between somatoform disorder and anxiety is complex. Much stronger evidence is needed before St. John's wort should be considered a treatment option for patients with diagnosable anxiety disorders.

HAWTHORN AND CALIFORNIA POPPY

A single French study exists of a combination product called Sympathyl,22 which contains 20 mg California poppy, 75 mg hawthorn, and 75 mg elemental magnesium. According to the study, Sympathyl had a very small but positive effect on anxiety. No clinical trials suggest that any of the individual components reduce anxiety in patients with anxiety disorders.

VALERIAN

Although valerian is often cited as having anxiolytic effects and has been used for centuries by herbalists/physicians to treat nervousness, there are only two small trials involving valerian, neither of which produced clear indications of effectiveness (Table 41623). Thus, at the present time, there is no clinical evidence of an anxiolytic effect of valerian when compared with placebo in patients with anxiety disorder.

PASSIONFLOWER

A single randomized double-blind trial compared 45 drops of passionflower tincture per day to 30 mg per day of oxazepam (Serax; brand no longer available in the United States) for 30 days.23 Investigators noted a marked reduction in anxiety score in both groups, but without a placebo group it was unclear whether other aspects of the milieu could have caused the effects.

Nutritional Supplements

Despite the number of nutritional supplements purported on the Internet to treat anxiety, only inositol, part of the vitamin B complex (B8) and an intracellular second messenger, has evidence suggesting superiority to placebo and even comparability with the SSRI fluvoxamine (Luvox; brand no longer available in the United States). Table 5 summarizes the evidence supporting the effectiveness and safety of inositol in managing anxiety disorders.2427

Inositol appears to have a positive effect on patients with panic disorder; however, its effect on patients with OCD is less clear. Physicians should inform patients that the limited data that exist to date suggest partial responses with a side-effect profile that may be comparable with that of SSRIs.

Table 5

Evidence Supporting the Effectiveness and Safety of Inositol in Anxiety Disorders

Design Description Comments

RCT crossover with placebo in panic disorder

Twenty-one patients with panic disorder were randomly assigned to 6 g of inositol or placebo twice a day for four weeks and then switched to the other substance24; during week 4, the mean number of panic attacks was 3.7 in the inositol group compared with 6.3 in the placebo group

Panic attack frequency and intensity were significantly reduced in the inositol group

RCT crossover with SSRI in panic disorder

Inositol was compared with fluvoxamine (Luvox) in 20 patients with panic disorder25; each crossover phase lasted four weeks (dosage: inositol, 18 g per day, or fluvoxamine, 150 mg per day); the four-week intervals were separated by a one-week placebo washout period; overall, both drugs reduced panic attack frequency and intensity, anxiety scale scores, and clinical global improvement scores; no meaningful clinical differences were noted between the two drugs

The absence of a placebo condition is troubling but, taken together with the previous trial, inositol appears to reduce panic disorder symptoms in the short term; over a one-month interval, inositol showed effectiveness similar to that of establishedSSRI medications for panic disorder

RCT crossover with placebo in OCD

The same research team compared inositol and placebo for the treatment of OCD26; 13 patients with OCD who had failed SSRI or clomipramine (Anafranil) treatments or who could not tolerate their side effects used 18 g per day of inositol or placebo for consecutive six-week treatment intervals; inositol produced significant reductions in Yale-Brown Obsessive-Compulsive Scale scores (4.6) compared with the placebo condition (0.3); reductions in Hamilton Anxiety Scale scores were not significantly different

Inositol appears to be highly effective in reducing OCD symptoms but not in reducing anxiety scale scores; participants with OCD had failed previous treatment, so findings may not be typical of patients with OCD in general

RCT crossover with placebo in OCD

Inositol added to SSRI treatments for OCD27; 13 patients with OCD who had not responded adequately to fluoxetine (Prozac), fluvoxamine, or clomipramine for at least eight weeks were given consecutive six-week trials on 18 g per day of inositol or placebo, in addition to the SSRI medication; inositol provided no additional benefit

The two studies on treatment-resistant OCD suggest inositol adds no benefit to SSRI therapy but may have positive effects on its own; none of these short studies produced side effects from inositol that would suggest risk greater than that of SSRIs


RCT = randomized controlled trial; SSRI = selective serotonin reuptake inhibitor; OCD = obsessive-compulsive disorder.

Information from references 24 through 27.

Table 5   Evidence Supporting the Effectiveness and Safety of Inositol in Anxiety Disorders

View Table

Table 5

Evidence Supporting the Effectiveness and Safety of Inositol in Anxiety Disorders

Design Description Comments

RCT crossover with placebo in panic disorder

Twenty-one patients with panic disorder were randomly assigned to 6 g of inositol or placebo twice a day for four weeks and then switched to the other substance24; during week 4, the mean number of panic attacks was 3.7 in the inositol group compared with 6.3 in the placebo group

Panic attack frequency and intensity were significantly reduced in the inositol group

RCT crossover with SSRI in panic disorder

Inositol was compared with fluvoxamine (Luvox) in 20 patients with panic disorder25; each crossover phase lasted four weeks (dosage: inositol, 18 g per day, or fluvoxamine, 150 mg per day); the four-week intervals were separated by a one-week placebo washout period; overall, both drugs reduced panic attack frequency and intensity, anxiety scale scores, and clinical global improvement scores; no meaningful clinical differences were noted between the two drugs

The absence of a placebo condition is troubling but, taken together with the previous trial, inositol appears to reduce panic disorder symptoms in the short term; over a one-month interval, inositol showed effectiveness similar to that of establishedSSRI medications for panic disorder

RCT crossover with placebo in OCD

The same research team compared inositol and placebo for the treatment of OCD26; 13 patients with OCD who had failed SSRI or clomipramine (Anafranil) treatments or who could not tolerate their side effects used 18 g per day of inositol or placebo for consecutive six-week treatment intervals; inositol produced significant reductions in Yale-Brown Obsessive-Compulsive Scale scores (4.6) compared with the placebo condition (0.3); reductions in Hamilton Anxiety Scale scores were not significantly different

Inositol appears to be highly effective in reducing OCD symptoms but not in reducing anxiety scale scores; participants with OCD had failed previous treatment, so findings may not be typical of patients with OCD in general

RCT crossover with placebo in OCD

Inositol added to SSRI treatments for OCD27; 13 patients with OCD who had not responded adequately to fluoxetine (Prozac), fluvoxamine, or clomipramine for at least eight weeks were given consecutive six-week trials on 18 g per day of inositol or placebo, in addition to the SSRI medication; inositol provided no additional benefit

The two studies on treatment-resistant OCD suggest inositol adds no benefit to SSRI therapy but may have positive effects on its own; none of these short studies produced side effects from inositol that would suggest risk greater than that of SSRIs


RCT = randomized controlled trial; SSRI = selective serotonin reuptake inhibitor; OCD = obsessive-compulsive disorder.

Information from references 24 through 27.

Neurotransmitter Or Hormonal Precursors

The anxiolytic neurotransmitter or hormonal precursors with some evidence of effectiveness are shown in Table 1. The vast majority of neurotransmitter or hormonal precursors that claim to be useful for treating anxiety disorders have no evidence supporting clinical utility. Only 5-hydroxytryptophan appeared to show clinical effectiveness among the precursor preparations. Table 6 summarizes the available evidence relevant to the effectiveness and safety of 5-hydroxytryptophan.28,29

Table 6

Evidence Supporting the Effectiveness and Safety of 5-Hydroxytryptophan in Anxiety Disorders

Design Description Comments

RCT in panic disorder

Patients with panic disorder (n = 24) exposed to a panic-inducing carbon dioxide challenge were given a single dose of 5-hydroxytryptophan (200 mg) or placebo before exposure28; patients with panic disorder showed a significantly lower occurrence of panic symptoms; patients without panic disorder did not show any significant effects of the carbon dioxide challenge

This small trial compared patient responses to an artificial panic-inducing challenge; it is not clear if the panic prevention effect would transfer to real-world situations

RCT on mixed anxiety disorders

Double-blind placebo-controlled trial on 45 mixed anxiety disorders, mostly panic attacks with agoraphobia, compared 5-hydroxytryptophan withclomipramine (Anafranil) and placebo for eight weeks29; the clomipramine and 5-hydroxytryptophan were titrated from 25 mg a day to a maximum of 150 mg per day; the clomipramine group showed significant reductions in Hamilton Anxiety Scale scores compared with placebo, whereas the 5-hydroxytryptophan group showed modest, nonsignificant improvements

No clinically meaningful effect of 5-hydroxytryptophan on reducing anxiety scale scores

Case reports on safety

In the past, multiple cases of eosinophilia-myalgia syndrome were reported among l-tryptophan users; this serious, incurable, potentially fatal neurologic condition motivated the temporary withdrawal of serotonin precursors from the market; the pattern of cases suggested they came from a single brand of contaminated l-tryptophan

l-tryptophan products are back on the market; there is current speculation that any brand of L-tryptophan or l-hydroxytryptophan can elicit this serious side effect in overdose


RCT = randomized controlled trial.

Information from references 28and 29.

Table 6   Evidence Supporting the Effectiveness and Safety of 5-Hydroxytryptophan in Anxiety Disorders

View Table

Table 6

Evidence Supporting the Effectiveness and Safety of 5-Hydroxytryptophan in Anxiety Disorders

Design Description Comments

RCT in panic disorder

Patients with panic disorder (n = 24) exposed to a panic-inducing carbon dioxide challenge were given a single dose of 5-hydroxytryptophan (200 mg) or placebo before exposure28; patients with panic disorder showed a significantly lower occurrence of panic symptoms; patients without panic disorder did not show any significant effects of the carbon dioxide challenge

This small trial compared patient responses to an artificial panic-inducing challenge; it is not clear if the panic prevention effect would transfer to real-world situations

RCT on mixed anxiety disorders

Double-blind placebo-controlled trial on 45 mixed anxiety disorders, mostly panic attacks with agoraphobia, compared 5-hydroxytryptophan withclomipramine (Anafranil) and placebo for eight weeks29; the clomipramine and 5-hydroxytryptophan were titrated from 25 mg a day to a maximum of 150 mg per day; the clomipramine group showed significant reductions in Hamilton Anxiety Scale scores compared with placebo, whereas the 5-hydroxytryptophan group showed modest, nonsignificant improvements

No clinically meaningful effect of 5-hydroxytryptophan on reducing anxiety scale scores

Case reports on safety

In the past, multiple cases of eosinophilia-myalgia syndrome were reported among l-tryptophan users; this serious, incurable, potentially fatal neurologic condition motivated the temporary withdrawal of serotonin precursors from the market; the pattern of cases suggested they came from a single brand of contaminated l-tryptophan

l-tryptophan products are back on the market; there is current speculation that any brand of L-tryptophan or l-hydroxytryptophan can elicit this serious side effect in overdose


RCT = randomized controlled trial.

Information from references 28and 29.

Although there is some indication that 5-hydroxytryptophan can reduce anxiety symptoms among patients with anxiety disorders, the evidence is weak. Also, it has been known to cause eosinophiliamyalgia syndrome, a significantly dangerous side effect. Therefore, the risk/benefit ratio does not favor physician support of patients choosing this medication because it is “natural.”

Key Recommendations for Physicians

Because use of herbal remedies is increasing, it is important for family physicians to ask their patients about such use. Encouraging data support the effectiveness of some of these products, particularly kava and, to a lesser degree, inositol. Although none of these supplements or products are free of adverse effects, the potential for benefit seems greater than the risk of harm.

The existing data show that the popular supplements St. John's wort, valerian, and omega-3 fatty acids have little therapeutic value for anxiety disorders, and their use should be discouraged in favor of more effective treatments. In addition, many preparationsthat might be used by patients to reduce anxiety lack evidence of effectiveness with anxiety disorders. The availability of natural treatments that are supported by clinical evidence and the recognition of those that are not will help physicians collaborate with patients using or seeking natural remedies to maximize the potential for benefit and minimize the potential for harm.

The Authors

SY ATEZAZ SAEED, MD, is a professor and chairman of the Department of Psychiatric Medicine, Brody School of Medicine at East Carolina University, Greenville, N.C., and chief of psychiatry at Pitt Memorial Hospital, Greenville. Dr. Saeed received his medical degree from Dow Medical College, Karachi, Pakistan, and completed his residency training in psychiatry at the Illinois State Psychiatric Institute, Chicago.

RICHARD M. BLOCH, PhD, is a professor and director of research in the Department of Psychiatric Medicine, Brody School of Medicine at East Carolina University. Dr. Bloch received his doctorate in psychology from the University of Wisconsin, Madison.

DIANA J. ANTONACCI, MD, is professor and director of residency training in the Department of Psychiatric Medicine, Brody School of Medicine at East Carolina University. Dr. Antonacci received her medical degree from Southern Illinois University School of Medicine, Springfield; completed her residency training in psychiatry at Duke University Medical Center, Durham, N.C.; and served a fellowship in child and adolescent psychiatry at East Carolina University.

Address correspondence to Sy Atezaz Saeed, MD, Dept. of Psychiatric Medicine, Brody School of Medicine at East Carolina University, 600 Moye Blvd., Suite 4E-100, Greenville, NC 27834. Reprints are not available from the authors.

Author disclosure: Nothing to disclose.

REFERENCES

1. Eisenberg DM, Davis RB, Ettner SL, Appel S, Wilkey S, Van Rompay M, et al. Trends in alternative medicine use in the United States, 1990–1997: results of a follow-up national survey. JAMA. 1998;280:1569–75.

2. Unutzer J, Klap R, Sturm R, Young AS, Marmon T, Shatkin J, et al. Mental disorders and the use of alternative medicine: results from a national survey. Am J Psychiatry. 2000;157:1851–7.

3. Kessler RC, Soukup J, Davis RB, Foster DF, Wilkey SA, Van Rompay MI, et al. The use of complementary and alternative therapies to treat anxiety and depression in the United States. Am J Psychiatry. 2001;158:289–94.

4. Pittler MH, Ernst E. Kava extract for treating anxiety. Cochrane Database Syst Rev. 2003;(1):CD003383.

5. Witte S, Loew D, Gaus W. Meta-analysis of the efficacy of the acetonic kava-kava extract WS1490 in patients with non-psychotic anxiety disorders. Phytother Res. 2005;19:183–8.

6. Connor KM, Payne V, Davidson JR. Kava in generalized anxiety disorder: three placebo-controlled trials. Int Clin Psychopharmacol. 2006;21:249–53.

7. Boerner RJ, Sommer H, Berger W, Kuhn U, Schmidt U, Mannel M. Kava-kava extract LI 150 is as effective as opipramol and buspirone in generalised anxiety disorder—an 8-week randomized, double-blind multi-centre clinical trial in 129 outpatients. Phytomedicine. 2003;(10 suppl 4):38–49.

8. Volz HP, Kieser M. Kava-kava extract WS 1490 versus placebo in anxiety disorders—a randomized placebo-controlled 25-week outpatient trial. Pharmacopsychiatry. 1997;30:1–5.

9. Connor KM, Davidson JR, Churchill LE. Adverse-effect profile of kava. CNS Spectr. 2001;6:848,850–3.

10. Clouatre DL. Kava kava: examining new reports of toxicity. Toxicol Lett. 2004;150:85–96.

11. Center for Food Safety and Applied Nutrition, U.S. Food and Drug Administration. Kava-containing dietary supplements may be associated with severe liver injury. Accessed March 20, 2007, at: http://www.cfsan.fda.gov/~dms/addskava.html.

12. Simkins A, Thurston D, Colyar M, Talbot S. Nature's wrath? A closer look at complications with five popular herbs. Adv Nurse Pract. 2005;13:55–6,58.

13. Singh YN. Potential for interaction of kava and St. John's wort with drugs. J Ethnopharmacol. 2005;100:108–13.

14. Singh YN, Singh NN. Therapeutic potential of kava in the treatment of anxiety disorders. CNS Drugs. 2002;16:731–43.

15. Ernst E. The risk-benefit profile of commonly used herbal therapies: ginkgo, St. John's wort, ginseng, echinacea, saw palmetto, and kava [Published correction appears in Ann Intern Med 2003;138:79]. Ann Intern Med. 2002;136:42–53.

16. Kobak KA, Taylor LV, Bystritsky A, Kohlenberg CJ, Greist JH, Tucker P, et al. St. John's wort versus placebo in obsessive-compulsive disorder: results from a double-blind study. Int Clin Psychopharmacol. 2005;20:299–304.

17. Taylor LH, Kobak KA. An open-label trial of St. John's wort (Hypericum perforatum) in obsessive-compulsive disorder. J Clin Psychiatry. 2000;61:575–8.

18. Kobak KA, Taylor LV, Warner G, Futterer R. St. John's wort versus placebo in social phobia: results from a placebo-controlled pilot study. J Clin Psychopharmacol. 2005;25:51–8.

19. Volz HP, Murck H, Kasper S, Moller HJ. St. John's wort extract (LI 160) in somatoform disorders: results of a placebo-controlled trial [Published correction appears in Psychopharmacology (Berl) 2003;167:333]. Psychopharmacology (Berl). 2002;164:294–300.

20. Muller D, Pfeil T, von den Driesch V. Treating depression comorbid with anxiety—results of an open, practice-oriented study with St. John's wort WS 5572 and valerian extract in high doses. Phytomedicine. 2003;(10 suppl 4):25–30.

21. Andreatini R, Sartori VA, Seabra ML, Leite JR. Effect of valepotriates (valerian extract) in generalized anxiety disorder: a randomized placebo-controlled pilot study. Phytother Res. 2002;16:650–4.

22. Hanus M, Lafon J, Mathieu M. Double-blind, randomised, placebo-controlled study to evaluate the efficacy and safety of a fixed combination containing two plant extracts (Crataegus oxyacantha and Eschscholtzia californica) and magnesium in mild-to-moderate anxiety disorders. Curr Med Res Opin. 2004;20:63–71.

23. Akhondzadeh S, Naghavi HR, Vazirian M, Shayeganpour A, Rashidi H, Khani M. Passionflower in the treatment of generalized anxiety: a pilot double-blind randomized controlled trial with oxazepam. J Clin Pharm Ther. 2001;26:363–7.

24. Benjamin J, Levine J, Fux M, Aviv A, Levy D, Belmaker RH. Double-blind, placebo-controlled, crossover trial of inositol treatment for panic disorder. Am J Psychiatry. 1995;152:1084–6.

25. Palatnik A, Frolov K, Fux M, Benjamin J. Double-blind, controlled, crossover trial of inositol versus fluvoxamine for the treatment of panic disorder. J Clin Psychopharmacol. 2001;21:335–9.

26. Fux M, Levine J, Aviv A, Belmaker RH. Inositol treatment of obsessive-compulsive disorder. Am J Psychiatry. 1996;153:1219–21.

27. Fux M, Benjamin J, Belmaker RH. Inositol versus placebo augmentation of serotonin reuptake inhibitors in the treatment of obsessive-compulsive disorder: a double-blind cross-over study. Int J Neuropsychopharmacol. 1999;2:193–5.

28. Schruers K, van Diest R, Overbeek T, Griez E. Acute L-5-hydroxytryptophan administration inhibits carbon dioxide-induced panic in panic disorder patients. Psychiatry Res. 2002;113:237–43.

29. Kahn RS, Westenberg HG, Verhoeven WM, Gispende Wied CC, Kamerbeek WD. Effect of a serotonin precursor and uptake inhibitor in anxiety disorders; a double-blind comparison of 5-hydroxytryptophan, clomipramine and placebo. Int Clin Psychopharmacol. 1987;2:33–45.


Copyright © 2007 by the American Academy of Family Physicians.
This content is owned by the AAFP. A person viewing it online may make one printout of the material and may use that printout only for his or her personal, non-commercial reference. This material may not otherwise be downloaded, copied, printed, stored, transmitted or reproduced in any medium, whether now known or later invented, except as authorized in writing by the AAFP. Contact afpserv@aafp.org for copyright questions and/or permission requests.

Want to use this article elsewhere? Get Permissions


Article Tools

  • Download PDF
  • Print page
  • Share this page
  • AFP CME Quiz

Information From Industry

More in Pubmed

Navigate this Article