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 Clinical Management Series
Natural Medicines in Clinical Management
of Insomnia
Sedative / Hypnotics | Antidepressants | Antihistamines
Miscellaneous | The Bottom Line | References
 

For millions of people insomnia is more than an occasional annoyance. It's a persistent problem with potentially serious consequences. Insomnia costs the U.S. and Canada over $100 billion annually in lost productivity and medical expenses. Insomnia also increases the risk of automobile accidents...about 100,000 car accidents and 1,500 deaths annually are attributed to drowsiness. Some experts believe that insomnia is as often to blame for car accidents as drunk driving.

Chronic insomnia might also lead to poor or worsening health in general...depression, headaches, heart disease, and substance abuse.

Patients typically have one of four types of insomnia: 1) difficulty falling asleep; 2) difficulty maintaining sleep; 3) early morning awakening; or 4) unrefreshing sleep. All types can cause daytime sleepiness and potentially decrease productivity and increase the risk of accidents, etc.

Insomnia is often a symptom of some underlying condition or situation (Table 1). Insomnia is frequently situational...caused by things like jet lag, shift work, or stress. It can also be caused by poor sleep habits, drinking alcohol, or by use of stimulants such as caffeine or other drugs. Certain medical conditions can also cause insomnia.12312,12313 Management of these underlying conditions will often relieve insomnia.

Table 1.  Common underlying causes of insomnia
Situational Causes
  • Daytime napping
  • Eating or exercising
    before sleep
  • Jet lag
  • Shift work
  • Stress
Medical Conditions
  • Angina
  • Depression
  • Hypoglycemia
  • Pain
  • Pregnancy
  • Anxiety
  • Gastrointestinal
    reflux
  • Internet addiction
  • Parkinson's
    disease
  • Restless leg
    syndrome
  • Arrhythmia
  • Heart failure
  • Mania or hypomania
  • Peptic ulcers
  • Sleep apnea
  • Asthma
  • Hyperthyroidism
  • Menopausal symptoms
  • Periodic limb
    movement disorder
Drugs*
  • Albuterol
  • Caffeine
  • Methyldopa
  • Phenylephrine
  • Tricyclic
    antidepressants
  • Alcohol
  • Clonidine
  • Methylphenidate
  • Pseudoephedrine
  • Antipsychotics
  • Corticosteroids
  • Methysergide
  • Quinidine
  • Beta-blockers
  • Dextroamphetamine
  • Nicotine
  • SSRI anti-
    depressants
  • Bupropion
  • Levodopa
  • Pemoline
  • Theophylline
Natural Medicines*
  • Alpha-GPC
  • American ginseng
    (Panax quinquefolius)
  • Bitter orange
    (Citrus aurantium)
  • Black tea
    (Camellia sinensis)
  • Citicoline
  • Cola nut
    (Cola acuminata)
  • Green tea
    (Camellia sinensis)
  • Guarana
    (Paullinia cupana)
  • Mate
    (Ilex paraguariensis)
  • Panax ginseng
  • Panax
    pseudoginseng
  • Phosphatidylserine
  • SAMe
  • Siberian ginseng
    (Eleutherococcus senticosus)
  • St. John's wort
    (Hypericum perforatum)
*Note: Not a complete listing

The elderly often complain of insomnia or are concerned that they aren't sleeping enough. It is true that as we get older, we tend to need less sleep than when we were younger. Explain to elderly patients that as long as they feel refreshed when they get up in the morning, they are getting enough sleep.

On the other hand, elderly people often don't sleep well at night due to an underlying medical condition or medications. This group tends to have daytime drowsiness and they compensate with daytime naps. That sets up a cycle or conditioning that reinforces poor sleep at night.

Lots of patients, not just the elderly, develop insomnia due to this type of conditioning. Patients begin to associate the bed with insomnia or wakefulness. They might have no trouble at all falling asleep in the living room in front of the TV. But when they fall asleep in a bed they wake up.

Commonly Used Conventional and Natural Medicines for Insomnia*
Sedative / Hypnotics
   Conventional Medicines
      Barbiturates
         Pentobarbital (Nembutol)
         Phenobarbital (Solfoton)
         Secobarbital (Seconal)
      Benzodiazepines
         Estazolam (Prosom)
         Diazepam (Valium)
         Flurazepam (Dalmane)
         Oxazepam (Serax)
         Temazepam (Restoril)
         Triazolam (Halcion)
      Non-benzodiazepines
         Eszopiclone (Lunestra)
         Zaleplon (Sonata)
         Zolpidem (Ambien)
         Zopiclone (Imovane; available in Canada)
      Others
         Chloral hydrate (Noctec)
         Meprobamate (Miltown)
   Natural Medicines
      German chamomile (Matricaria recutita)
      Hops (Humulus lupulus)
      Kava (Piper methysticum)
      Lavender (Lavandula angustifolia)
      Lemon balm (Melissa officinalis)
      Passionflower (Passiflora incarnata)
      Skullcap (Scutellaria lateriflora)
      Valerian (Valeriana officinalis)
Antidepressants
   Conventional Medicines
      Amitriptyline (Elavil)
      Doxepin (Sinequan)
      Trazodone (Desyrel)
   Natural Medicines
      St. John's wort (Hypericum perforatum)
Antihistamines
   Conventional Medicines
      Diphenhydramine (Benadryl)
      Doxylamine (Unisom)
Miscellaneous
   Natural Medicines
      5-HTP
      Coenzyme Q10
      L-tryptophan
      Melatonin
*Note: Many natural products are tried for insomnia, but very few have reliable evidence that they work. Inclusion in this list does NOT imply that these products are effective for insomnia.

Improving sleep habits is a good first step for everyone with insomnia (Table 2). But in some cases, improving sleep habits is not enough to break the cycle. Short-term drug therapy might be needed.

Table 2.  Good Sleep Habits
  • Stick to a regular sleep schedule-even on weekends. But if on some nights you're not sleepy at the regular time, don't go to bed until you are.
  • Exercise regularly, but avoid exercise late in the evening close to bedtime.
  • Put your worries away when you go to bed. Some people try writing them down, then crumpling up the paper, and tossing it in the waste basket.
  • Do something relaxing and enjoyable before bedtime.
  • Make your bedroom quiet and comfortable.
  • Avoid large meals just before bedtime.
  • Do not read or watch TV in bed. Reserve the bedroom for sleep and sexual activity.
  • If you cannot sleep within 15 to 20 minutes, get up and go to another room to read or do something relaxing. Return to bed only when drowsy.
  • Remove the clock from eyesight.
  • Do not nap during the day. If you must nap, limit it to 30 minutes in the early afternoon.
  • Reduce alcohol, nicotine, and caffeine use.
  • Avoid frequent use of sedatives.
  • Schedule outdoor time at the same time each day.

 
 
 
  Question #1
A 28-year-old patient tells you he can't sleep. He isn't taking any medications. There is no evidence of depression or any other underlying disease. What tips could you give him for a better night's sleep?
  • Sedative / Hypnoticsreturn to top 

    Sedative/hypnotic is a generic term for several classes of drugs, including barbiturates, benzodiazepines, and the newer non-benzodiazepine sedatives.

    Benzodiazepines such as diazepam (Valium) and temazepam (Restoril) have been the gold-standard therapy for insomnia for a long time. The benzodiazepines bind nonselectively to benzodiazepine-1 and -2 receptors. This affects gamma-aminobutyric acid (GABA) in the central nervous system and causes central nervous system depression. Benzodiazepines can reduce time to sleep onset, number of nighttime awakenings, and increase total sleep time.12312

    The newer short-acting non-benzodiazepine drugs are now the drugs of choice for short-term treatment of insomnia. These include zolpidem (Ambien) and zaleplon (Sonata). Zopiclone (Imovane) is also available in Canada. Recently, eszopiclone (Lunestra), an isomer of zopiclone, was approved in the U.S. Eszopiclone is the first one to be approved for long-term use in insomnia.

    These drugs work similar to benzodiazepines, but act selectively at just the benzodiazepine-1 receptor. Compared with benzodiazepines, they cause less tolerance, rebound insomnia, and hangover effects. They all reduce time to sleep onset, sometimes called sleep latency. Zolpidem also increases total sleep time and efficiency.

    Before seeing their physician for one of these prescription drugs, many patients self-treat with natural medicines. As many as 26% of patients with insomnia are trying them.12315

    Many natural medicines have effects on the central nervous system similar to the prescription sedative/hypnotics.

    You have probably heard of valerian (Valeriana officinalis). It is one of the most popular natural medicines used for insomnia. And it's also one of the most studied. Valerian seems to have benzodiazepine-like effects. The valerenic acid constituent might increase GABA activity in the central nervous system by inhibiting an enzyme that metabolizes GABA.3486

    Taking valerian extract does seem to reduce the time to sleep onset in many patients with insomnia.6248,6249,8250,8296 But valerian doesn't seem to work as fast as benzodiazepines. Several nights to a few weeks may be needed for it to work.6249,10209

    Valerian seems to be safe when used short-term and it's well tolerated. Most patients don't experience morning sleepiness or the hangover effect that is sometimes experienced with benzodiazepines.2074

    Valerian is promising, but there's still not enough solid evidence to recommend it for most patients. If a patient wants to try it, don't worry too much. Help them use it appropriately.

    Advise these patients to use the formulation used in the studies...extracts standardized to contain 0.4-0.6% of the constituent valerenic acid. These should be taken in doses of 400-900 mg/day 2 hours before bedtime.

    Suggest short-term use. Like other drugs used for insomnia, valerian shouldn't be used for longer than 30 days. There's not enough evidence about long-term safety. There are also a few cases of hepatotoxicity in patients who have taken valerian.3484,8243 So far it's not clear if valerian was the cause, however, if patients take valerian for an extended period of time, liver function monitoring should be recommended.

    There is some concern about drug interactions. In a test tube study, valerian inhibited the cytochrome P450 3A4 enzyme.6450 This means that valerian could potentially increase levels of drugs metabolized by this enzyme. But it's too soon to know for sure if valerian has this effect in humans...and if it does, how significant it is. For now, just keep a look out for signs of potential interactions. Some drugs metabolized by CYP3A4 include lovastatin (Mevacor), ketoconazole (Nizoral), itraconazole (Sporanox), fexofenadine (Allegra), triazolam (Halcion), chemotherapeutic agents (etoposide, paclitaxel, vinblastine, vincristine, vindesine), and many others.

    Practice Pearl
    Tell patients who have taken valerian long-term in high doses, not to stop it suddenly. It should be slowly discontinued...similar to benzodiazepines. There's some concern that valerian might cause a benzodiazepine-like withdrawal syndrome if discontinued suddenly.3487

    There are lots of combination product "sleep formulas" on store shelves. Many of these combine valerian with a variety of other herbs such as hops, lavender, lemon balm, and skullcap. Many of these have sedative properties. But there's no reliable evidence that they improve insomnia...or that the combinations are any more effective than valerian when used alone.

    German chamomile (Matricaria recutita) is a very popular "bedtime tea." There's no doubt that chamomile can cause some sedation. Just ask anyone who's consumed it. They'll likely tell you that it makes them feel calm and relaxed. But that doesn't necessarily translate into effectiveness for insomnia. So far there's no reliable evidence that it's effective for insomnia.

    Like valerian, there is some concern about drug interactions. German chamomile might inhibit the cytochrome P450 3A4 enzyme...and potentially increase levels of drug metabolized by this enzyme.6450 But it's too soon to know for sure if German chamomile has this effect in humans. Be alert for signs of interactions in patients who take German chamomile.

    Practice Pearl
    Warn patients with ragweed or similar allergies that they might also be allergic to chamomile.567

    Passionflower (Passiflora incarnata) used to be marketed as an OTC sleep aid. But in 1978 it was taken off the U.S. market due to lack of safety and effectiveness data. It's now marketed as a dietary supplement...usually used as a tea. Passionflower seems to cause sedation, possibly by affecting benzodiazepine receptors.4001 But so far there's no scientifically reliable evidence it helps for insomnia.

    Kava (Piper methysticum) is best known as a treatment for anxiety. But it is also often used for insomnia. It does have sedative properties and has been shown to be effective for anxiety.2093,2094,2095,7325,11372 But it hasn't been shown to be effective for patients with insomnia.

    Tell patients to avoid kava. Not only is there no proof it helps for insomnia, it is also unsafe. Kava has been linked to over 60 cases of hepatotoxicity. It's already been banned in several countries.7024,7068,7086,7096 So far all of these cases have been linked to kava extracts containing concentrated amounts of the active kavalactones in capsule or tablet form. There have not been reports of liver damage in people who occasionally consume kava tea. But until more is known, discourage patients from using kava products.

    Practice Pearl
    Advise patients against combining sedative natural medicines with conventional sedative/hypnotic drugs. The combination might cause excessive sedation and cognitive impairment.

    		 
    View brands containing:
    -Valerian
      Question #2
    Valerian is primarily used for insomnia. But it is also used for another condition and is rated Possibly Effective
  •   Question #3
    Which statement about the effectiveness of valerian is TRUE?
  • View brands containing:
    -Hops
    -Lavender
    -Lemon balm
    -Skullcap
    -German
    chamomile
      Question #4
    Which statement about the safety of valerian is TRUE?
  • View brands containing:
    -Passionflower
    -Kava
      Question #5
    True or False. Sleep formula combination products are more effective for insomnia than valerian alone.
  •   Question #6
    Chamomile tea is a popular bedtime tea. What advice should you give to patients who are interested in using it for insomnia?
  • Antidepressantsreturn to top 

    Low-dose sedative antidepressants are also used. These are most helpful for people who wake up during the night...and especially if they suffer from depression.12312,12314 These antidepressants include amitriptyline (Elavil), doxepin (Sinequan), and trazodone (Desyrel).

    St. John's wort (Hypericum perforatum) is the famous herbal antidepressant. It is likely effective for mild to moderate depression. And there's some evidence it improves insomnia in depressed patients.376 But there's no evidence that it is effective for insomnia in patients who are not depressed.

    Keep in mind that St. John's wort can be stimulating for some patients. In fact, one of its most common side effects is INSOMNIA.3569 Tell patients not to take it at bedtime until they know how it affects them.

    Drug interactions are also a HUGE concern in anyone who uses St. John's wort. It is a potent INDUCER of cytochrome P450 3A4. It can decrease levels and the effectiveness of lots of drugs. Some of these include the HIV protease inhibitors, non-nucleoside reverse transcriptase inhibitors, oral contraceptives, cyclosporin, some statins, and many others.

    Practice Pearl
    Tell women who take St. John's wort that if they use oral contraceptives for birth control to use a back up method of contraception. St. John's wort can decrease the effectiveness of oral contraceptives which could result in unexpected pregnancy.11886,11887

    		 
      Question #7
    A patient is interested in trying kava for insomnia. Which of the following is TRUE?
  • View brands containing:
    -St. John's wort
    Antihistaminesreturn to top 

    In addition to natural medicines, many patients self-treat insomnia with over-the-counter sleep remedies. Most often these are the antihistamines diphenhydramine (Benadryl, Sominex) or doxylamine (Unisom). They have sedative effects, but are less effective than benzodiazepines. They can also cause significant anticholinergic side effects...orthostatic hypotension, urinary retention, and confusion, which can be especially problematic for the elderly.12312,12313 There is also concern that they might decrease sleep quality. In general, OTC antihistamines should be discouraged for routine use for insomnia.

    		 
      Question #8
    A patient calls and explains that she is pregnant despite taking an oral contraceptive. Which of the following natural medicines that she is taking is most likely to be responsible for her unexpected pregnancy?
  • Miscellaneousreturn to top 

    Melatonin is one of the best known supplements for sleep. It's tried by lots of people with insomnia, but its effectiveness is controversial. Melatonin is a naturally occurring hormone produced in the pineal gland. Endogenous melatonin regulates circadian rhythms. Darkness seems to stimulate melatonin secretion and light inhibits it.1773 Melatonin levels are thought to be lower than normal in some patients with insomnia.6498

    The best evidence for melatonin suggests that it improves insomnia in the elderly, especially if melatonin levels are low.1072,1729,1738,1754,7081 Younger patients also report subjective improvement in sleep quality when taking melatonin. But melatonin does not seem to improve objective measures of sleep such as sleep latency in these patients.1068,1070,1083

    Melatonin might be worth a try for select patients... particularly older adults. Suggest a dose of 0.3-5 mg/day. If patients try it, suggest that they only use it short-term. If it doesn't work after a few weeks, it's probably not going to help, and there's not much known about the safety of long-term use.

    Practice Pearl
    Suggest immediate-release melatonin for people with difficulty falling asleep. For difficulty staying asleep, suggest sustained-release melatonin.1738,1754

    Melatonin precursors are also being used for insomnia...L-tryptophan and 5-HTP. L-tryptophan is converted to 5-HTP, which is converted to serotonin...and then melatonin. But there is no reliable evidence that either of these products works for insomina. BOTH products should be avoided due to the risk for eosinophil-myalgia syndrome (EMS).9,512,902,919 L-tryptophan was taken off the U.S. market in 1990 due to more than 1500 cases of EMS. 5-HTP is still available, but there are concerns about possible contamination with "peak x" which has been linked to EMS.

    Coenzyme Q10 seems to help people with insomnia related to congestive heart failure. Some heart failure patients have insomnia related to nocturnal dyspnea. Adjunctive use of coenzyme Q10 can decrease the dyspnea and other symptoms...and therefore might help improve sleep.6409 Coenzyme Q10 might be worth a try in patients with heart failure. But make sure patients don't self-treat this serious condition. They should talk it over with their healthcare provider first.

    		 
    View brands containing:
    -Melatonin
      Question #9
    Melatonin is very popular for sleep related disorders including insomnia and jet lag. Because it is easily available OTC, many patients may not consider its potential for drug interactions. Which patients should you steer away from melatonin because of these risks? (HINT: click on the melatonin link above to go to the monograph - then scroll to the Interactions with Drugs section)
  • View brands containing:
    -L-tryptophan
    -5-HTP
    -Coenzyme Q-10
    The Bottom Linereturn to top 

    Many people don't seek medical advice for treatment of insomnia. They often choose self-treatment with OTC drugs or natural medicines. Whether patients are trying OTC drugs or natural medicines, warn them about using sleep aids chronically. Chronic use can build reliance on them. And after long-term use, rebound insomnia can occur when the sleep aid is stopped.

    It's too soon to recommend most natural medicines promoted for insomnia. There just isn't enough evidence in most cases. And there certainly isn't any evidence that suggests they are more effective or better tolerated than the newer non-benzodiazepine sedatives like zolpidem (Ambien).

    Melatonin probably isn't appropriate for all patients with insomnia. But it might be worth a trial run for some people with insomnia, particularly elderly patients.

    Advise patients using any sedative (prescription, OTC, or natural) that they have the potential to cause impairment. Patients should be advised against operating a vehicle after taking these products.

    Also caution patients against combining multiple sedatives. Combining natural sedatives with prescription or OTC products could lead to excessive sedation.

    		 
      Question #10
    A patient asks what natural medicine you would recommend for insomnia. Which of the following represents good advice based on the scientific evidence?
  •   
     
    Recommendation Chart for Natural Medicines Used for Insomnia *
    Safety/EffectiveLikely
    Safe    		Possibly
    Safe    		Insufficient
    Evidence    		Possibly
    Unsafe    		Likely
    Unsafe    		Unsafe
    Effective      
    Likely
    Effective
    -St. John's
    wort
    (depression related insomnia)
         		     
    Possibly
    Effective
    -Coenzyme
    Q-10
    (CHF related insomnia)
    -Melatonin
     
    -Valerian
         		    
    Insufficient
    Evidence    		 
    -German
    chamomile
    -Hops
    -Lavender
    -Lemon balm
    -Passion-
    flower
     
    -Skullcap
     
    -5-HTP
    -Kava
         		 
    -L-trypto-
    phan
     
    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
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    376Hubner WD, Lande S, Podzuweit H. Hypericum treatment of mild depressions with somatic symptoms. J Geriatr Psychiatry Neurol 1994;7 Suppl 1:S12-4.
    512Robbers JE, Tyler VE. Tyler's Herbs of Choice: The Therapeutic Use of Phytomedicinals. New York, NY: The Haworth Herbal Press, 1999.
    567Subiza J, Subiza JL, Hinojosa M, et al. Anaphylactic reaction after the ingestion of chamomile tea; a study of cross-reactivity with other composite pollens. J Allergy Clin Immunol 1989;84:353-8.
    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.
    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
    1068Attenburrow ME, Cowen PJ, Sharpley AL. Low dose melatonin improves sleep in healthy middle-aged subjects. Psychopharmacol (Berl) 1996;126:179-81.
    1070Ellis CM, Lemmens G, Parkes JD. Melatonin and insomnia. J Sleep Res 1996;5:61-5.
    1072Garfinkel D, et al. Improvement of sleep quality in elderly people by controlled-release melatonin. Lancet 1995;346:541-44.
    1083James SP, Sack DA, Rosenthal NE, Mendelson WB. Melatonin administration in insomnia. Neuropsychopharmacol 1990;3:19-23.
    1729Brusco LI, Fainstein I, Marquez M, et al. Effect of melatonin in selected populations of sleep-disturbed patients. Biol Signals Recept 1999;8:126-31.
    1738Haimov I, Lavie P, Laudon M, et al. Melatonin replacement therapy of elderly insomniacs. Sleep 1995;18:598-603.
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    1773Brzezinski A. Melatonin in humans. N Engl J Med 1997;336:186-95.
    2074Kuhlmann J, Berger W, Podzuweit H, Schmidt U. The influence of valerian treatment on "reaction time, alertness and concentration" in volunteers. Pharmacopsychiatry 1999;32:235-41.
    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.
    3484Klepser TB, Klepser ME. Unsafe and potentially safe herbal therapies. Am J Health Syst Pharm 1999;56:125-38.
    3486Houghton PJ. The scientific basis for the reputed activity of Valerian. J Pharm Pharmacol 1999;51:505-12.
    3487Garges HP, Varia I, Doraiswamy PM. Cardiac complications and delirium associated with Valerian root withdrawal. [Letter to the Editor] JAMA 1998;280:1566-7.
    3569Beckman SE, Sommi RW, Switzer J. Consumer use of St. John's wort: A survey of effectiveness, safety, and tolerability. Pharmacotherapy 2000;20:568-74.
    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.
    6248Leathwood PD, Chauffard F, Heck E, Munoz-Box R. Aqueous extract of valerian root (Valeriana officinalis L.) improves sleep quality in man. Pharmacol Biochem Behav 1982;17:65-71.
    6249Donath F, Quispe S, Diefenbach K, et al. Critical evaluation of the effect of valerian extract on sleep structure and sleep quality. Pharmacopsych 2000;33:47-53.
    6409Baggio E, Gandini R, Plauncher AC, et al. Italian multicenter study on the safety and efficacy of coenzyme Q10 as adjunctive therapy in heart failure. CoQ10 Drug Surveillance Investigators. Mol Aspects Med 1994;15 Suppl:S287-94.
    6450Budzinski JW, Foster BC, Vandenhoek S, et al. An in vitro evaluation of human cytochrome P450 3A4 inhibition by selected commercial herbal extracts and tinctures. Phytomedicine 2000;7:273-82.
    6498von Bahr C, Ursing C, Yasui N, et al. Fluvoxamine but not citalopram increases serum melatonin in healthy subjects – an indication that cytochrome P450 CYP1A2 and CYP2C19 hydroxylate melatonin. Eur J Clin Pharmacol 2000;56:123-7.
    7024Escher M, Desmeules J, Giostra E, Mentha G. Drug Points: hepatitis associated with kava, a herbal remedy for anxiety. BMJ 2001;322:139.
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    7081Zhdanova IV, Wurtman RJ, Regan MM, et al. Melatonin treatment for age-related insomnia. J Clin Endocrinol Metab 2001;86:4727-30.
    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.
    8243MacGregor FB, Abernethy VE, Dahabra S, et al. Hepatotoxicity of herbal remedies. BMJ 1989;299:1156-7.
    8250Bent S, Patterson M, Garvin D. Valerian for sleep: a systematic review and meta-analysis. Alternative Therapies 2001;7:S4.
    8296Leathwood PD, Chauffard F. Aqueous extract of valerian reduces latency to fall asleep in man. Planta Med 1985;2:144-8.
    10209Stevinson C, Ernst E. Valerian for insomnia: a systematic review of randomized clinical trials. Sleep Med 2000;1:91-9.
    11372Pittler MH, Ernst E. Kava extract for treating anxiety. Cochrane Database Syst Rev 2003;(1):CD003383.
    11886Pfrunder A, Schiesser M, Gerber S, et al. Interaction of St John's wort with low-dose oral contraceptive therapy: a randomized controlled trial. Br J Clin Pharmacol 2003;56:683-90.
    11887Hall SD, Wang Z, Huang SM, et al. The interaction between St John's wort and an oral contraceptive. Clin Pharmacol Ther 2003;74:525-35.
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    12314Arana GW, Hyman SE. Handbook of Psychiatric Drug Therapy. 2nd edition. Boston, MA: Little, Brown & Company, 1991.
    12315Rostler S. More studies should target health effects of sleep herbs. Reuters Health, June 15, 2000.
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