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Natural Medicines in the Clinical Management of Anxiety
Antidepressants | Sedatives/Hypnotics/Anxiolytics | The Bottom Line
References
 

Anxiety disorders are the most prevalent psychiatric disorders in North America.13781 This is not the simple nervousness or anxiousness that we all experience. This anxiety is persistent, unremitting, or debilitating, and generally beyond the control of the patient.

When people say "anxiety" they usually mean generalized anxiety disorder (GAD) or panic disorder. But conditions such as obsessive-compulsive disorder (OCD), post-traumatic stress disorder (PTSD), and specific phobias are also classified as anxiety disorders. GAD is the most common form of anxiety. It has a lifetime prevalence of 4.1% to 6.6%. It is more common in women than men.13781

Anxiety and other psychiatric conditions such as depression often occur together. Symptoms of anxiety can also occur in other conditions such as depression and schizophrenia.

Anxiety is sometimes triggered by identifiable events or activities:
  • Traumatic experience: natural disaster, automobile accident, war, etc.
  • Drugs
  • Stressful situations: illness, death of a loved one, finances, family issues, etc.
  • Endocrine imbalance: hyperthyroid state, premenstrual syndrome, etc.
For many patients there is not an obvious cause for anxiety. These patients may have certain neurotransmitter imbalances. An abnormal noradrenergic or serotonergic response to stressful events can cause excessive anxiousness and worry. Severe somatic symptoms can also develop such as palpitations, tremors, and hyperventilation. Drug therapy for anxiety targets these neurotransmitter imbalances.

Some Drugs that can Induce or Exacerbate Anxiety*
Drug Class Example
Stimulants Albuterol
Caffeine
Pseudoephedrine
Methylphenidate
Anorexiants Phentermine
Sibutramine
Antihistamines Diphenhydramine (idiosyncratic)
Antipsychotics Haloperidol
Diuretics Acetazolamide
*Not a complete list.

Commonly Used Conventional and Natural Medicines for Anxiety*
Antidepressants
  • Conventional Medicines
    • Citalopram (Celexa)
    • Desipramine (Norpramin)
    • Duloxetine (Cymbalta)
    • Escitalopram (Lexapro)
    • Fluoxetine (Prozac)
    • Fluvoxamine (Luvox)
    • Imipramine (Tofranil)
    • Mirtazapine (Remeron)
    • Nefazodone (Serzone - only available generically)
    • Nortriptyline (Pamelor)
    • Paroxetine (Paxil)
    • Trazodone (Desyrel)
    • Venlafaxine (Effexor)
  • Natural Medicines
Sedatives/Hypnotics/Anxiolytics
  • Conventional Medicines
    • Benzodiazepines (alprazolam, etc)
    • Buspirone (Buspar)
  • Natural Medicines
*Note: Many natural products are tried for anxiety, but very few have reliable evidence that they work. Inclusion in this list does NOT imply that these products are effective for anxiety.

 
 
 
  Question #1
Which of the following might trigger or exacerbate anxiety?
  • Antidepressantsreturn to top 

    Antidepressants are used for GAD, panic disorder, obsessive-compulsive disorder (OCD), specific phobias, and post-traumatic stress disorder (PTSD). Tricyclic antidepressants (TCAs), selective serotonin reuptake inhibitors (SSRIs), and mixed reuptake inhibitors (e.g., venlafaxine, duloxetine, etc) are effective. But SSRIs and mixed reuptake inhibitors are more widely used because they are better tolerated than the TCAs.

    FDA-Approved Anxiety Indications of Select Antidepressants
    Drug GAD Panic Disorder OCD PTSD Social Anxiety
    Citalopram (Celexa)     X X  
    Duloxetine (Cymbalta) X        
    Escitalopram (Lexapro) X        
    Fluvoxamine (Luvox)     X    
    Fluvoxamine extended release (Luvox CR)     X   X
    Venlafaxine (Effexor XR) X X     X
    Fluoxetine (Prozac)   X X    
    Sertraline (Zoloft)   X X X X
    Paroxetine (Paxil) X X X X X

    For more information on conventional antidepressants get the Pharmacist's Letter / Prescriber's Letter chart, Comparison of Commonly Used Antidepressants.

    Several natural medicines are also thought to have antidepressant effects. Several are tried for anxiety as well.

    St. John's wort is a popular alternative to conventional antidepressants. Extracts of St. John's wort seem to inhibit the reuptake of serotonin, norepinephrine, and dopamine.763,3553,4521,6427,6474,8936,11408 It might also inhibit uptake of GABA and L-glutamate.3553,4521

    Most scientific evidence for St. John's wort relates to its use for depression. But there is some research in patients with OCD. Preliminary evidence from an open-label study suggested that a specific St. John's wort extract standardized to 0.3% hypericin (Alterra, Upsher-Smith Laboratories) 450 mg twice daily for 12 weeks might improve symptoms of OCD.5075 However, a higher quality, blinded study using a different St. John's wort extract (LI 160, Lichtwer Pharma) 600-1800 mg/day suggests that it does not significantly improve symptoms of OCD.14417 The reason for contradictory findings could be due to differences in study design, study duration, differences in the St. John's wort products used, or other factors.

    For now, don't recommend St. John's wort for patients with OCD.

    Practice Pearl
    St. John's wort can be stimulating to some patients just like conventional antidepressants. Lower doses of antidepressants are sometimes used to avoid this problem. Advise anxiety patients that St. John's wort could potentially exacerbate anxiety.

    Keep in mind that St. John's wort can interact with a lot of drugs. It INDUCES cytochrome P450 3A4 and p-glycoprotein and therefore can DECREASE levels of drugs metabolized by this enzyme...amitriptyline (Elavil), cyclosporine (Neoral, Sandimmune), digoxin (Lanoxin), HIV protease inhibitors and non-nucleoside reverse transcriptase inhibitors (NNRTIs), nortriptyline (Pamelor), oral contraceptives, theophylline, warfarin (Coumadin), and many others.

    Practice Pearl
    St. John's wort might decrease the effectiveness of oral contraceptives. Advise patients taking oral contraceptives to use an alternate form of birth control if they take St. John's wort.

    Another popular alternative to convention antidepressants is S-adenosyl-L-methionine, better known as SAMe. It seems to affect levels of dopamine, norepinephrine, and serotonin. Imaging studies suggest that it affects brain activity similar to conventional antidepressants.5196,5232,9110,9114 SAMe is effective for depression, but so far, there is no reliable evidence that it works for anxiety disorders. Don't recommend it.

    Some patients are trying 5-hydroxytryptophan (5-HTP) or its relative, L-tryptophan. These two compounds are closely related. L-tryptophan is metabolized to 5-HTP, which is then metabolized to 5-hydroxytryptamine, better known as serotonin. Not surprisingly, taking either L-tryptophan or 5-HTP increases CNS levels of serotonin.10853,10857 Both substances also have some evidence to suggest that they might help for depression.903,6245,10853,10856 And there is very preliminary evidence that 5-HTP might be beneficial for anxiety disorders.915 But this evidence is too preliminary to recommend either substance for any anxiety disorder.

    There are also concerns about the safety of both L-tryptophan and 5-HTP. Years ago these products were linked to several cases of eosinophilia myalgia syndrome (EMS).902,919,7067,8053,10084,10085,11474,11478 Until more is known about the safety of 5-HTP and L-tryptophan, tell patients not to use them.

    		 
    View brands containing:
    -St. John's wort
      Question #2
    A 25 year old female patient with generalized anxiety wants to use St. John's wort to help her feel better. She currently takes Loestrin FE (an oral contraceptive) and a calcium supplement. What should you tell her?
  •   Question #3
    Which of the following has some preliminary research suggesting that it might help for obsessive-compulsive disorder (OCD)?
  • View brands containing:
    -SAMe
    -5-HTP
    -L-tryptophan
      Question #4
    Which of the following has been linked to L-tryptophan?
  • Sedatives/Hypnotics/Anxiolyticsreturn to top 

    Benzodiazepines (diazepam, alprazolam, lorazepam, etc) are often used for anxiety disorders. Benzodiazepines are especially effective for quick symptom relief in patients who have GAD or panic disorder. They are also a good symptom relieving bridge while patients wait for other medications such as SSRIs to kick in.

    Benzodiazepines target gamma-aminobutyric acid (GABA), the major inhibitory neurotransmitter in the CNS. GABA is also involved in regulating other neurotransmitters like norepinephrine and serotonin. Benzodiazepines work by potentiating the effects of GABA.

    Since patients can develop tolerance to these benzodiazepines, they are usually only appropriate for short-term treatment.

    Buspirone (Buspar) is also used primarily for GAD. It is not a benzodiazepine, but shares some of the properties of benzodiazepines for relieving anxiety. Buspirone doesn't work quickly like benzos. It needs to be taken consistently for several weeks.

    There is also a lot of interest in herbal alternatives.

    Kava is one of the best known herbs for anxiety. Kava tea has a long history of use among Pacific Islanders where it is used during social and religious ceremonies. Islanders say it has a "calming" effect and promotes sociability. In Europe and North America, kava extract capsules are now a popular treatment for anxiety.

    Kava extracts are often standardized to contain 10% to 70% kava lactones. Kava extracts are thought to have a variety of effects including anxiolytic, sedative, anticonvulsant, and analgesic. Kava does not seem to affect benzodiazepine receptors, but it might increase the effects of GABA by increasing GABA binding sites.640,4037, 4038,9923,11373

    Kava extracts standardized to contain 70% kava lactones do reduce symptoms of anxiety. Most clinical research shows that they work about as well as low-dose benzodiazepines.2092,2093,2094,2095,7325,11372,15130 It's not known if extracts that contain a lower concentration of kava lactones are as effective.

    Kava is not fast-acting like benzodiazepines. Kava can take up to 8 weeks before it provides significant benefit.2094,2095

    Kava has been safely used in clinical trials, short-term. But there is concern that kava extracts might not be safe. There are over 60 case reports of hepatotoxicity.7024,7068,7086,7096,11795 Hepatotoxicity can occur in some patients after as little as 3-4 weeks of use, even in normal doses. "Slow metabolizers" or those patients deficient in cytochrome P450 2D6 are theorized to be more susceptible.7068

    Due to these safety concerns, kava has been banned from the market in Switzerland, Germany, Canada, and several other countries. Many more countries are considering similar action.

    Advise patients not to use kava.

    Patients are also using passionflower and valerian as bedtime teas to help relieve stress and anxiety and facilitate sleep.

    Passionflower contains apigenin, which seems to bind the GABA receptor.4001 There is preliminary evidence that taking a passionflower liquid extract 45 drops might be as effective as the benzodiazepine oxazepam (Serax) 30 mg daily for GAD.8007 But oxazepam is not a good choice for comparison because it is not commonly used for anxiety. More evidence is needed before passionflower can be recommended.

    Valerian seems to inhibit metabolism of GABA, which boosts GABA levels in the CNS.3486,12720 There is some clinical research that suggest valerian can also decrease social anxiety and GAD.9893,9895,9896 However, other evidence suggests no benefit.15046 Like passionflower, more evidence is needed before valerian can be recommended.

    Skullcap has a long history of use for relieving stress and tension and helping people feel calm and relaxed. Flavonoids contained in skullcap seem to bind to GABA receptors and have an anxiolytic and sedative effect. People who take skullcap do tend to feel more relaxed.12216 But there is no reliable evidence that it can treat anxiety disorders. Don't recommend it.

    Theanine is now showing up in various dietary supplements. Theanine is the major amino acid of green tea. It has a variety of interesting properties, but has been used for anxiety. Theanine is thought to increase levels of serotonin and GABA.12188

    There is preliminary evidence that theanine helps people feel more tranquil, but no reliable evidence that it helps for anxiety disorders.12188

    Practice Pearl
    Many of the natural products used for anxiety have sedating effects. Advise patients who take them to avoid driving or performing other dangerous tasks after taking these products.

    		 
    View brands containing:
    -Kava
      Question #5
    Which of the following would be most appropriate to tell a patient who is interested in taking kava?
  •   Question #6
    A patient has been taking kava for 3 months for anxiety. She complains that she has recently been feeling fatigued. Which of the following would be MOST appropriate to recommend?
  • View brands containing:
    -Passionflower
    -Valerian
      Question #7
    A patient diagnosed with GAD is taking alprazolam (Xanax). She tells you that she heard that the herb valerian is "good for calming nerves." Which of the following is TRUE? (HINT: Review the valerian monograph to find the correct answer.)
  • View brands containing:
    -Skullcap
    -Theanine
      Question #8
    A patient tells you that he is taking a skullcap extract 250 mg daily for anxiety. Which of the following side effects would this patient be likely to experience? (HINT: Review the Adverse Reactions section of the skullcap monograph to find the correct answer.)
  • The Bottom Linereturn to top 

    Drug therapy with antidepressants and benzodiazepines is only one component of the treatment for anxiety. The best approach to treatment usually includes a combination of drug therapy plus stress management, relaxation techniques, and behavioral medicine or psychotherapy. No single approach works for all patients.

    Some patients will ask about adding or substituting natural medicines. Even though some natural products have some evidence of benefit, none have adequate evidence of safety or effectiveness to recommend.

    If patients decide to use natural products, help them use the products safely. If patients use St. John's wort, watch for drug interactions. If patients use kava, suggest regular liver function tests. Caution patients that many of these products can be sedating and could be unsafe to use before driving or performing other dangerous tasks.

    		 
      Question #9
    Which of the following has been associated with hepatotoxicity?
  •   Question #10
    Which of the following is an appropriate choice for treating generalized anxiety disorder?
  •   
     
    Recommendation Chart for Natural Medicines Used for Anxiety *
    Safety/EffectiveLikely
    Safe    		Possibly
    Safe    		Insufficient
    Evidence    		Possibly
    Unsafe    		Likely
    Unsafe    		Unsafe
    Effective      
    Likely
    Effective    		      
    Possibly
    Effective    		 
    -Passionflower
         		 
    -Kava
         		  
    Insufficient
    Evidence
    -St. John's wort
    -SAMe
     
    -Theanine
    -Valerian
     
    -Skullcap
     
    -5-HTP
    -L-Tryptophan
         		  
    Possibly
    Ineffective    		      
    Likely
    Ineffective    		      
    Ineffective      
     KEY:
     Consider recommending this product.
     Don't recommend using this product.
     Recommend against using this product.

    * These proposed recommendations are based solely on the Safety and Effectiveness Ratings contained in Natural Medicines Comprehensive Database. This assumes use of high-quality, uncontaminated products and the use of typical doses. Keep in mind that some products are never appropriate for some patients due to concomitant disease states, potential drug interactions, or other clinical factors. Use your clinical judgment before recommending any product.

    References return to top
    640Castot A, Djezzar S, Deleau N, et al. [Pharmacovigilance off the beaten track: herbal surveillance or pharmacovigilance of medicinal plants]. [Article in French]. Therapie 1997;52:97-103.
    763Muller WE, Singer A, Wonnemann M, et al. Hyperforin represents the neurotransmitter reuptake inhibiting constituent of hypericum extract. Pharmacopsychiatry 1998;31:16-21.
    902Michelson D, Page SW, Casey R, et al. An eosinophilia-myalgia syndrome related disorder associated with exposure to L-5-hydroxytryptophan. J Rheumatol 1994;21:2261-5.
    903Nakajima T, Kudo Y, Kaneko Z. Clinical evaluation of 5-hydroxy-L-tryptophan as an antidepressant drug. Folia Psychiatr Neurol Jpn 1978;32:223-30.
    915Kahn RS, Westenberg HGM. L-5-hydroxytryptophan in the treatment of anxiety disorders. J Affect Disord 1985;8:197-200.
    919FDA Talk Paper. Impurities confirmed in dietary supplement 5-hydroxy-L-tryptophan. August 31, 1998. Available at: http://vm.cfsan.fda.gov/~lrd/tp5htp.html
    2092Woelk H, Kapoula O, Lehrl S, et al. [Comparison of kava special extract WS 1490 and benzodiazepines in patients with anxiety]. [Article in German]. Z Allg Med 1993;69:271–7.
    2093Pittler MH, Ernst E. Efficacy of kava extract for treating anxiety: systematic review and meta-analysis. J Clin Psychopharmacol 2000;20:84-9.
    2094Volz 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.
    2095Lehmann E, Kinzler E, Friedemann J. Efficacy of a special Kava extract (Piper methysticum) in patients with states of anxiety, tension and excitedness of non-mental origin- a double-blind placebo-controlled study of four weeks treatment. Phytomedicine 1996;3:113-9.
    3486Houghton PJ. The scientific basis for the reputed activity of Valerian. J Pharm Pharmacol 1999;51:505-12.
    3553Singer A, Wonnemann M, Muller WE. Hyperforin, a major antidepressant constituent of St. John's wort, inhibits serotonin uptake by elevating free intracellular Na+11. J Pharmacol Exp Ther 1999;290:1363-8.
    4001Salgueiro JB, Ardenghi P, Dias M, et al. Anxiolytic natural and synthetic flavonoid ligands of the central benzodiazepine receptor have no effect on memory tasks in rats. Pharmacol Biochem Behav 1997;58:887-91.
    4037Jussofie A, Schmiz A, Hiemke C. Kavapyrone enriched extract from Piper methysticum as modulator of the GABA binding site in different regions of rat brain. Psychopharmacology 1994;116:469-74.
    4038Davies LP, Drew CA, Duffield P, et al. Kava Pyrones and Resin: Studies on GABA-A, GABA-B, and Benzodiazepine Binding Sites in Rodent Brain. Pharmacol Toxicol 1992;71:120-6.
    4521Jensen AG, Hansen SH, Nielsen EO. Adhyperforin as a contributor to the effect of Hypericum perforatum L. in biochemical models of antidepressant activity. Life Sci 2001;68:1593-605.
    5075Taylor 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.
    5196Rosenbaum JF, Fava M, Falk WE, et al. The antidepressant potential of oral S-adenosyl-l-methionine. Acta Psychiatr Scand 1990;81:432-6.
    5232Bottiglieri T, Hyland K, Reynolds EH. The clinical potential of ademetionine (S-adenosylmethionine) in neurological disorders. Drugs 1994;48:137-52.
    6245Nardini M, De Stefano R, Iannuccelli M, et al. Treatment of depression with L-5-hydroxytryptophan combined with chlorimipramine, a double-blind study. Int J Clin Pharmacol Res 1983;3:239-50.
    6427Kleber E, Obry T, Hippeli S, et al. Biochemical activities of extracts from Hypericum perforatum L. Arzneimittelforschung 1999;49:106-9.
    6474Vormfelde SV, Poser W. Hyperforin in extracts of St. John's wort (Hypericum perforatum) for depression [letter]. Arch Intern Med 2000;160:2548.
    7024Escher M, Desmeules J, Giostra E, Mentha G. Drug Points: hepatitis associated with kava, a herbal remedy for anxiety. BMJ 2001;322:139.
    7067FDA. Information paper on L-tryptophan and 5-hydroxy-L-tryptophan. Office of Nutritional Products, Labeling, Dietary Supplements. Center for Food Safety and Applied Nutrition. February 2001.
    7068Russmann S, Lauterberg BH, Hebling A. Kava hepatotoxicity [letter]. Ann Intern Med 2001;135:68.
    7086Liver Toxicity with kava. Pharmacist's Letter/Prescriber's Letter 2001;18(1):180115.
    7096Consultation letter MLX 286: Proposals to prohibit the herbal ingredient Kava-Kava (Piper methysticum) in unlicensed medicines. Medicines Control Agency, United Kingdom, July 19, 2002.
    7325Malsch U, Kieser M. Efficacy of kava-kava in the treatment of non-psychotic anxiety, following pretreatment with benzodiazepines. Psychopharmacology (Berl) 2001;157:277-83.
    8007Akhondzadeh S, Naghavi HR, Shayeganpour A, et al. Passionflower in the treatment of generalized anxiety: a pilot double-blind randomized controlled trial with oxazepam. J Clin Pharm Ther 2001;26:363-7.
    8053Sullivan EA, Kamb ML, Jones JL, et al. The natural history of eosinophilia-myalgia syndrome in a tryptophan-exposed cohort in South Carolina. Arch Intern Med 1996;156:973-9.
    8936Calapai G, Crupi A, Firenzuoli F, et al. Serotonin, norepinephrine and dopamine involvement in the antidepressant action of hypericum perforatum. Pharmacopsychiatry 2001;34:45-9.
    9110Bottiglieri T. S-Adenosyl-L-methionine (SAMe): from the bench to the bedside--molecular basis of a pleiotrophic molecule. Am J Clin Nutr 2002;76:1151S-7S.
    9114Saletu B, Anderer P, Di Padova C. Electrophysiological neuroimaging of the central effects of S-adenosyl-L-methionine by mapping of electroencephalograms and event-related potentials and low-resolution brain electromagnetic tomography. Am J Clin Nutr 2002;76:1162S-71S.
    9893Cropley M, Cave Z, Ellis J, Middleton RW. Effect of kava and valerian on human physiological and psychological responses to mental stress assessed under laboratory conditions. Phytother Res 2002;16:23-7.
    9895Kohnen R, Oswald WD. The effects of valerian, propranolol, and their combination on activation, performance and mood of healthy volunteers under social stress conditions. Pharmacopsychiatry 1988;21:447-8.
    9896Andreatini 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.
    9923Baum SS, Hill R, Rommelspacher H. Effect of kava extract and individual kavapyrones on neurotransmitter levels in the nucleus accumbens of rats. Prog Neuropsychopharmacol Biol Psychiatry 1998;22:1105-1120.
    10084Johnson KL, Klarskov K, Benson LM, et al. Presence of peak X and related compounds: the reported contaminant in case related 5-hydroxy-L-tryptophan associated with eosinophilia-myalgia syndrome. J Rheumatol 1999;26:2714-7.
    10085Greenberg AS, Takagi H, Hill RH, et al. Delayed onset of skin fibrosis after the ingestion of eosinophilia-myalgia syndrome-associated L-tryptophan. J Am Acad Dermatol 1996;35:264-6.
    10853Shaw K, Turner J, Del Mar C. Tryptophan and 5-hydroxytryptophan for depression. Cochrane Database Syst Rev 2002;(1):CD003198.
    10856Walinder J, Skott A, Carlsson A, et al. Potentiation of the antidepressant action of clomipramine by tryptophan. Arch Gen Psychiatry 1976;33:1384-89.
    10857van Praag HM. Management of depression with serotonin precursors. Biol Psychiatry 1981;16:291-310.
    11372Pittler MH, Ernst E. Kava extract for treating anxiety. Cochrane Database Syst Rev 2003;(1):CD003383.
    11373Cairney S, Maruff P, Clough AR, et al. Saccade and cognitive impairment associated with kava intoxication. Hum Psychopharmacol 2003;18:525-33.
    11408Schule C, Baghai T, Ferrera A, Laakmann G. Neuroendocrine effects of Hypericum extract WS 5570 in 12 healthy male volunteers. Pharmacopsychiatry 2001;34:S127-33.
    11474Kilbourne EM, Philen RM, Kamb ML, Falk H. Tryptophan produced by Showa Denko and epidemic eosinophilia-myalgia syndrome. J Rheumatol Suppl 1996;46:81-8.
    11478Carr L, Ruther E, Berg PA, Lehnert H. Eosinophilia-myalgia syndrome in Germany: an epidemiologic review. Mayo Clin Proc 1994;69:620-5.
    11795Gow PJ, Connelly NJ, Hill RL, et al. Fatal fulminant hepatic failure induced by a natural therapy containing kava. Med J Aust 2003;178:442-3.
    12188Lu K, Gray MA, Oliver C, et al. The acute effects of L-theanine in comparison with alprazolam on anticipatory anxiety in humans. Hum Psychopharmacol Clin Exp 2004;19:457–65.
    12216Wolfson P, Hoffmann DL. An investigation into the efficacy of Scutellaria lateriflora in healthy volunteers. Altern Ther Health Med 2003;9:74-8.
    12720Yuan CS, Mehendale S, Xiao Y, et al. The gamma-aminobutyric acidergic effects of valerian and valerenic acid on rat brainstem neuronal activity. Anesth Analg 2004;98:353-8.
    13781Gliatto MF. Generalized anxiety disorder. Am Fam Physician 2000;62:1591-1600,1602.
    14417Kobak KA, Taylor LV, Bystritsky A, 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.
    15046Jacobs BP, Bent S, Tice JA, et al. An internet-based randomized, placebo-controlled trial of kava and valerian for anxiety and insomnia. Medicine (Baltimore) 2005;84:197-207.
    15130Connor KM, Payne V, Davidson JR. Kava in generalized anxiety disorder: three placebo-controlled trials. Int Clin Psychopharmacol 2006;21:249-53.
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