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Natural Medicines in the 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 is a persistent problem with potentially serious consequences. Insomnia costs the US 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 another underlying condition or situation. 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.

Common Underlying Causes of Insomnia*
Situational Causes
  • Daytime napping
  • Eating or exercising before sleep
  • Jet lag
  • Shift work
  • Stress
  
Medical Conditions
  • Angina
  • Anxiety
  • Arrhythmia
  • Asthma
  • Depression
  • Gastrointestinal reflux
  • Heart failure
  • Hyperthyroidism
  • Hypoglycemia
  • Internet addiction
  • Mania or hypomania
  • Menopausal symptoms
  • Pain
  • Parkinson's disease
  • Peptic ulcers
  • Periodic limb movement disorder
  • Pregnancy
  • Restless leg syndrome
  • Sleep apnea
Drugs
  • Albuterol
  • Alcohol
  • Antipsychotics
  • Beta-blockers
  • Bupropion
  • Caffeine
  • Clonidine
  • Corticosteroids
  • Dextroamphetamine
  • Levodopa
  • Methyldopa
  • Methylphenidate
  • Methysergide
  • Nicotine
  • Pemoline
  • Phenylephrine
  • Pseudoephedrine
  • Quinidine
  • SSRI antidepressants
  • Theophylline
  • Tricyclic antidepressants
Natural Medicines
  • Alpha-GPC
  • American ginseng
  • Bitter orange
  • Black tea
  • Citicoline
  • Cola nut
  • Green tea
  • Guarana
  • Mate
  • Panax ginseng
  • Panax pseudoginseng
  • Phosphatidylserine
  • SAMe
  • Siberian ginseng
  • St. John's wort
*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 likely 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 have difficulty getting to sleep in their bed.

Commonly Used Conventional and Natural Medicines for Insomnia*
Sedative/Hypnotics
  • Conventional Medicines
    • Barbiturates
      • Pentobarbital (Nembutal)
      • Phenobarbital (Luminal)
      • Secobarbital (Seconal)
    • Benzodiazepines
      • Diazepam (Valium)
      • Estazolam (ProSom)
      • Flurazepam (Dalmane)
      • Oxazepam (Serax)
      • Temazepam (Restoril)
      • Triazolam (Halcion)
    • Non-benzodiazepines
      • Eszopiclone (Lunesta)
      • Ramelteon (Rozerem)
      • Zaleplon (Sonata)
      • Zolpidem (Ambien)
      • Zopiclone (Imovane; available in Canada)
    • Others
      • Chloral hydrate (Noctec)
      • Meprobamate (Equanil)
Antidepressants
  • Conventional Medicines
    • Amitriptyline (Elavil)
    • Doxepin (Sinequan)
    • Trazodone (Desyrel)
Antihistamines
  • Conventional Medicines
    • Diphenydramine (Bendryl)
    • Doxylamine (Unisom)
Miscellaneous
*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. But in some cases, improving sleep habits is not enough to break the cycle. Short-term drug therapy might be needed.

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
An elderly man explains to you that he has difficulty falling asleep. A review of his medical record shows that he suffers from hypertension, anxiety and depression, and erectile dysfunction. His medication profile includes bupropion (Wellbutrin), sildenafil (Viagra), benazepril (Lotensin), and aspirin. Which of the following could be contributing to his insomnia?
  •   Question #2
    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/hypnotics 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 treatment of insomnia. These include zolpidem (Ambien), zaleplon (Sonata), zopiclone (Imovane; available in Canada), and eszopiclone (Lunesta).

    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.

    Get more information about these medications:

    Another newer non-benzodiazepine sedative/hypnotic is ramelteon (Rozerem). It's different than the other agents because it does not affect the benzodiazepine receptor. Instead, it is a melatonin receptor agonist. It is also not considered a controlled substance. There is less concern about abuse or dependence compared to the other agents.

    Get more information about Rozerem in Pharmacist's Letter / Prescriber's Letter.

    Find out how all of these conventional medications compare in the Pharmacist's Letter / Prescriber's Letter chart: Comparison of Insomnia Treatments.

    Before seeking a prescription medication, 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

    Some clinical research shows that taking valerian extract reduces the time to sleep onset in many patients with insomnia.6248,6249,8250,8296 But valerian doesn't 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. It's usually well tolerated. Most patients don't experience morning sleepiness or the hangover effect that is sometimes experienced with benzodiazepines.2070

    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 These are extracts standardized to contain 0.4% to 0.6% of the constituent valerenic acid. These should be taken in doses of 400-900 mg/day 2 hours before bedtime.

    There are a few cases of hepatotoxicity in patients who have taken valerian.3484,8243 So far it's not clear if valerian is the cause; however, if patients take valerian for an extended period of time, consider recommending liver function tests.

    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 lookout for signs of potential interactions.

    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 and there is some preliminary clinical research for some of these combinations.

    Preliminary clinical research shows that taking a specific combination product containing hops extract 41.9 mg plus valerian extract 187 mg per tablet, two tablets at bedtime, modestly improves subjective sleep measures including subjective sleep latency compared to placebo after 28 days of treatment.15018

    There is also preliminary clinical research that shows that a specific combination product, providing lemon balm leaf extract 80 mg and valerian root extract 160 mg (Euvegal forte, Schwabe Pharmaceuticals) 1-2 tablets once or twice daily, might decrease symptoms in children under age 12 years who have pathological restlessness or dyssomnia.14416

    These combinations look promising, but there is no reliable evidence that they are any more effective than valerian alone.

    German chamomile (Matricaria recutita) is a very popular "bedtime tea." There's no doubt that chamomile can cause some mild 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 over-the-counter sleep aid. But in 1978 it was taken off the US market due to lack of safety and effectiveness data. It's now marketed as a dietary supplement and is 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 does not seem to be effective for insomnia.15046

    Tell patients to avoid kava. Not only is there no proof it helps for insomnia, it is also possibly unsafe. Kava has been linked to over 60 cases of hepatotoxicity.7024,7068,7086,7096 Kava has been banned in several countries, but is still available in the US.

    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 #3
    A patient wants to use valerian for insomnia. Which of the following is appropriate advice?
  •   Question #4
    A patient asks you if valerian is safe to take with her medications. Her medications include: atorvastatin (Lipitor), Loestrin FE, and omeprazole (Prilosec). Which of the following medications might interact with valerian? (HINT: Click here to go to the Drug / Herb Interaction Checker. Enter valerian and each of the patient's medications to complete an interaction screening.)
  •   Question #5
    Which statement about valerian is TRUE?
  • View brands containing:
    -Hops
    -Lavender
    -Lemon balm
    -Skullcap
    -Valerian
    -German chamomile
    -Passionflower
    -Kava
      Question #6
    True or False. Sleep formula combination products are more effective for insomnia than valerian alone.
  •   Question #7
    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 #8
    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 #9
    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. In the body, L-tryptophan is converted to 5-HTP, which is converted to serotonin...and then melatonin. But there is no reliable evidence that these work for insomnia and there are concerns about safety.

    In 1989, more than 1500 cases of eosinophilia-myalgia syndrome (EMS) and 37 deaths were associated with L-tryptophan use in the US. About 95% of all EMS cases were traced to L-tryptophan produced by a single manufacturer in Japan. In 1990, L-tryptophan was recalled in the US and an FDA alert was put into force limiting the importation of all over-the-counter L-tryptophan products.7067,11477,11478 After the limitation of L-tryptophan products, the incidence of EMS dropped abruptly.11474 Under the Dietary Supplement Health and Education Act (DHSEA) of 1994, L-tryptophan is currently available and marketed as a dietary supplement.

    There is also concern that 5-HTP, like L-tryptophan, can cause eosinophilia and eosinophilia myalgia syndrome (EMS).902,919,7067 There is speculation that many commercial 5-HTP products may contain contaminants from the peak X family, a group of impurities that might cause EMS.919,10084 However, the presence of the peak X family or other contaminants has not been verified in all cases of EMS.

    Until the questions about EMS and long-term safety of 5-HTP and L-tryptophan supplements are resolved, patients should avoid using these products.

    Coenzyme Q-10 seems to help people with insomnia related to heart failure. Some heart failure patients have insomnia related to nocturnal dyspnea. Adjunctive use of coenzyme Q-10 can decrease the dyspnea and other symptoms…and therefore might help improve sleep.6409 Coenzyme Q-10 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 #10
    A patient asks what natural medicine you would recommend for insomnia. Which of the following represents good advice based on the scientific evidence?
  • View brands containing:
    -L-tryptophan
    -5-HTP
    -Coenzyme Q-10
    The Bottom Linereturn to top 

    Many people don't seek medical advice for treating 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. After long-term use, rebound insomnia can often occur when the sleep aid is stopped.

    It's too soon to recommend most natural medicines promoted for insomnia. There just isn't enough reliable 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.

    		 
      
     
    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)
    (depression related insomnia)
         		     
    Possibly
    Effective
    -Coenzyme Q-10
    (CHF-related insomnia)
    -Melatonin
     
    -Valerian
         		    
    Insufficient
    Evidence    		 
    -German chamomile
    -Hops
    -Lavender
    -Lemon balm
    -Passionflower
     
    -Skullcap
     
    -5-HTP
    -Kava
         		 
    -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
    376Hubner WD, Lande S, Podzuweit H. Hypericum treatment of mild depressions with somatic symptoms. J Geriatr Psychiatry Neurol 1994;7 Suppl 1:S12-4.
    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.
    1754Garfinkel D, Laudon M, Nof D, et al. Improvement of sleep quality in elderly people by controlled-release melatonin. Lancet 1995;346:541-4.
    1773Brzezinski A. Melatonin in humans. N Engl J Med 1997;336:186-95.
    2070Tacket CO, Binion SB, Bostwick E, et al. Efficacy of bovine milk immunoglobulin concentrate in preventing illness after Shigella flexneri challenge. Am J Trop Med Hyg 1992;47:276-83.
    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.
    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.
    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.
    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.
    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.
    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.
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