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REVIEW ARTICLES |
Division of Health Service Research, Institute of Psychiatry, and Division of Psychiatry, Homerton University Hospital
Division of Psychiatry, Homerton University Hospital
Unit for Social and Community Psychiatry, Barts and The London, NHS Trust, Queen Mary School of Medicine and Dentistry, London, UK
Correspondence: Dr Ursula Werneke, Division of Psychiatry, Homerton University Hospital, East Wing, Homerton Row, London E9 6SR, UK. E-mail: Ursula.Werneke{at}elcmht.nhs.uk
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ABSTRACT |
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Aims To review the complementary medicines routinely encountered in psychiatric practice, their effectiveness, potential adverse effects and interactions.
Method Electronic and manual literature search on the effectiveness and safety of psychotropic complementary medicines.
Results Potentially useful substances include ginkgo and hydergine as cognitive enhancers, passion flower and valerian as sedatives, St Johns wort and s-adenosylmethionine as antidepressants, and selenium and folate to complement antidepressants. The evidence is less conclusive for the use of omega-3 fatty acids as augmentation treatment in schizophrenia, melatonin for tardive dyskinesia and 18-methoxycoronaridine, an ibogaine derivative, for the treatment of cocaine and heroin addiction.
Conclusions Systematic clinical trials are needed to test promising substances. Meanwhile, those wishing to take psychotropic complementary medicines require appropriate advice.
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INTRODUCTION |
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Complementary medicines can be grouped into herbal remedies, food supplements, including vitamin preparations, and other organic and inorganic substances, including omega-3 fatty acids. Some people take food supplements and vitamin preparations in high doses, often outside the safety margins recommended by the Food Standards Agency (Food Standards Agency, 2003). People with mental health problems may take complementary medicines to treat anxiety and depression or to counter side-effects of conventional treatments, for example tardive dyskinesia and weight gain. Some seek a more holistic approach to treatment, others hope that complementary medicines have fewer or no side-effects, and many with chronic anxiety and depression understandably feel disillusioned by the apparent ineffectiveness of conventional treatment. The aim of this review is to acquaint psychiatrists with the complementary medicines routinely encountered in clinical practice, to review the evidence base for their purported effectiveness and to discuss potential adverse effects and interactions.
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METHOD |
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RESULTS |
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Cognitive enhancers
Cognitive enhancers are either used in the treatment of dementia to enhance
mental performance or to prevent cognitive decline in healthy people. This can
be achieved by increasing choline availability in the brain, e.g. by
inhibiting acetylcholinesterase. Alternative non-cholinergic neuroprotective
strategies have been postulated; these include antioxidants scavenging free
radicals, thereby reducing neurotoxicity, and anticoagulants increasing
cerebral blood flow (Spinella,
2001). Suggested herbal cognitive enhancers include ginkgo,
ginseng, hydergine, which is an ergot (Claviceps purpurea)
derivative, and solanceous plants, including potatoes, tomatoes and aubergines
(Table 1).
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Although in some individuals with Alzheimers disease ginkgo biloba has been reported to improve cognitive performance (Birks et al, 2002; Kanowski & Hoerr, 2003), another trial did not show any benefit in elderly people with Alzheimers disease of vascular type or age-associated cognitive impairment (van Dongen et al, 2003). Whether the effect in those with Alzheimers disease is equivalent to that of synthetic cholinesterase inhibitors is debatable (Itil et al, 1998; Wettstein, 2000; Schreiter-Gasser & Gasser, 2001). Hydergine was reported to lead to significant improvement of cognitive impairment in dementia, but most studies were performed before standardised dementia criteria were agreed (Olin et al, 2001). The results for panax ginseng and vitamin E were inconclusive (Sano et al, 1997; Vogeler et al, 1999). Solanaceous plants may exercise strong cholinergic effects by inhibiting not only acetyl- but also butyrylcholinesterase. However, no clinical studies have been conducted to determine their effects on cognition. They may augment cocaine toxicity via the same mechanism (Krasowski et al, 1997).
Anxiolytics and sedatives
Anxiolytics and sedatives essentially have the same underlying mechanisms
of action. The stronger the agent the greater the sedative effect, leading to
coma in extreme cases. Four mechanisms of action have been implicated
(Spinella, 2001): (a) binding
to gamma-aminobutyric acid (GABA) receptors leading to hyperpolarisation of
the cell membrane through increased influx of chlorine anions; (b) inhibition
of excitatory amino acids, thereby also impairing the ability to form new
memories; (c) sodium channel blockade, decreasing depolarisation of the cell
membrane; and (d) calcium channel blockade, decreasing the release of
neurotransmitters into the synaptic cleft. Most complementary medicines
prescribed for anxiolysis/sedation (e.g. kava kava, valerian, passion flower
and chamomile) are GABAergic, though for some such as hops the mechanism of
action remains unknown. As expected, all remedies can lead to drowsiness when
taken in high doses and can potentiate the effect of synthetic sedatives
(Table 2).
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The most researched substance is kava kava (Piper methysticum), which originated from Polynesia and was traditionally used for religious rituals (Chevallier, 1996). Kava has an anxiolytic effect that has been established in several RCTs (Pittler & Ernst, 2003). Kava has been associated with several cases of liver toxicity (Natural Medicines Database, 2004a), which has led to its voluntary withdrawal from the UK market. Valerian (Valeriana officinalis or Valeriana edulis) is a sedative believed to have been known to Galen and Dioscorides, which has maintained its importance throughout the centuries (Spinella, 2001). In 1845, Coffin described it as an excellent sedative... predisposing the mind to quietness and the body to sleep. Valerian may have comparable efficacy to oxazepam (Dorn, 2000; Ziegler et al, 2002). However, a systematic review on the effectiveness of valerian in insomnia produced inconclusive results (Stevinson & Ernst, 2000).
Passion flower (Passiflora incarnata) contains chrysin, a partial agonist to benzodiazepine receptors. One study comparing passion flower with oxazepam found both to be equally effective (Akhondzadeh et al, 2001a); more trials are needed to confirm the effect. No data are available on chamomile and hops. Chamomile (Chamaemelum nobile or Matricaria recutita) contains apigenin which binds to benzodiazepine receptors (Viola et al, 1995). The mechanism of action for hops (Humulus lupulus) remains unclear. Bach flower remedies are a combination of 38 flowers and seem to have no effect (Ernst, 2002). Melatonin extracted from the pineal gland may improve sleep in those with delayed sleep phase disorder, but no benefit has been shown in the treatment of primary sleep disorder (MacMahon et al, 2005). It may also improve initial sleep quality in older adults with insomnia (Olde Rikkert & Rigaud, 2001), but its role as a treatment for insomnia in those with Alzheimers disease remains disputed (Cardinali et al, 2002; Singer et al, 2003).
Antidepressants and augmentation therapy
All known synthetic antidepressants act via the enhancement of serotonergic
and noradrenergic neurotransmission. Most complementary antidepressants are
thought to work through the same pathways (Tables
3 and
4). The mechanism of action for
selenium is not clear but does seem to be different. Its antioxidant qualities
may reduce nerve cell damage (Benton,
2002), and it is also known to facilitate conversion from
thyroxine (T4) to thyronine (T3); T3 substitution is one possible means of
augmentation of antidepressants in conventional psychiatry. There are no
clinical studies but low selenium levels have been associated with depression,
anxiety and hostility (Hawkes &
Hornbostel, 1996), and high dietary intake or supplementation has
been associated with mood improvement. The apparent therapeutic effect may be
dose-dependent (Benton & Cook,
1991; Benton,
2002). Like lithium, there may be a narrow therapeutic index. A
recent report by the Food Standards Agency
(2003) reduced the recommended
limits of safe daily intake. Trials may be most promising in those with a low
baseline selenium level.
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The most robust clinical data are available for St Johns wort (Hypericum perforatum). These have been extensively reviewed in meta-analyses (Linde et al, 1996; Williams et al, 2000; Whiskey et al, 2001; Roder et al, 2004; Werneke et al, 2004b; Linde et al, 2005; Table 3) which have found a decrease in effect size over time when tested against placebo. The more recent meta-analyses mostly suggest that the effectiveness of St Johns wort is limited to mild depression, and more homogenous studies targeting patients with mild depression are required (Roder et al, 2004; Werneke et al, 2004b; Linde et al, 2005).
However, four of these meta-analyses have demonstrated equivalence to standard antidepressants (Linde et al, 1996; Whiskey et al, 2001; Roder et al, 2004; Linde et al, 2005). One recent trial using high doses (up to 1800 mg) of St Johns wort reported equivalence to paroxetine in those with moderate or severe depression (Szegedi et al, 2005). Hyperforin, which inhibits the reuptake of monoamines, is thought to be the most likely active component (Chatterjee et al, 1998; Müller et al, 1998). Thus, the use of extracts with maximum hyperforin content should be examined more systematically (Werneke et al, 2004b).
Folate and S-adenosylmethionine are in the same biochemical pathway, with folate being required to synthesise methionine, the direct precursor of S-adenosylmethionine, from homocysteine. S-adenosylmethionine facilitates many methylation reactions required for the synthesis of many neurotransmitters (Bottiglieri et al, 2000; Morris et al, 2003). Thus, those with high levels of homocysteine may be more likely to become depressed, or possibly less likely to respond to antidepressant treatment. Interestingly, hypothyroidism can lead to an increase in homocysteine levels (Roberts & Ladenson, 2004) and this may contribute to the associated depression. In clinical studies, folate has been reported to be effective only when added to antidepressant therapy (Taylor et al, 2004).
Parenteral S-adenosylmethionine has been reported to be superior to placebo (Bressa, 1994), and equivalence to imipramine has been demonstrated in two RCTs (Delle Chiaie et al, 2002; Pancheri et al, 2002). The onset of action may be more rapid (Fava et al, 1995). Oral S-adenosylmethionine may require doses four times as high as the parenteral formulation (Delle Chiaie et al, 2002). Finally, omega-3 fatty acids are known to stabilise membranes and to facilitate monoaminergic, serotonergic and cholinergic neurotransmission (Haag, 2003) but their antidepressant effect has not been convincingly demonstrated in clinical studies (Marangell et al, 2003; Su et al, 2003). Omega-3 fatty acids are possibly effective when added to lithium in the treatment of bipolar affective disorder (Bowden, 2001; Table 4).
Antipsychotics, augmentation and treatment of tardive dyskinesia
Only two complementary medicines have been suggested for the treatment of
psychosis. Rauwolfia (Rauwolfia serpentina) extracts were
traditionally used before synthetic antipsychotics became widely available,
several alkaloid derivatives, including reserpine, being introduced in the
1950s (Malamud et al,
1957). Rauwolfia originates from India and was mentioned in
Ayurvedic medicine around 700 BC
(Chevallier, 1996). It blocks
vesicular storage of monoamines, allowing them to be more easily degraded by
monoamine oxidases in the cytoplasm. As a consequence, the amount of
neurotransmitter available on depolarisation of the cell membrane is reduced
(Spinella, 2001), which may
lead to a reduction in dopamine and the resolution of psychotic symptoms.
However, serotonin and noradrenaline will also be less available, which
explains why reserpine readily precipitates depression. An alternative
strategy is the augmentation of antipsychotic treatment with omega-3 fatty
acids, but the results of clinical trials remain inconclusive
(Joy et al, 2003;
Table 5).
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Attempts have been made to treat tardive dyskinesia with vitamin E. This treatment strategy relies on the assumption that tardive dyskinesia not only results from dopamine receptor supersensitivity but is also related to the oxidative tissue damage of antipsychotic drugs (Shamir et al, 2001; Lohr et al, 2003). Meta-analysis of ten small trials has indicated that vitamin E protects against deterioration of tardive dyskinesia (Soares & McGrath, 2001); one recent trial has reported improvement (Zhang et al, 2004). A far more powerful antioxidant than vitamin E is melatonin, which attenuates the dopaminergic activity in the striatum as well as the release of dopamine from the hypothalamus (Shamir et al, 2001; Lohr et al, 2003). However, as with omega-3 fatty acids, clinical trials have been inconclusive (Shamir et al, 2000, 2001), and larger trials are required to test its therapeutic effectiveness (Table 5).
Anti-addictives
Although there are many addictive plants, few have been identified as
having the potential to counter addiction
(Table 6). Such may be
ibogaine, which is derived from the West African shrub Tabernanthe
iboga. It has hallucinogenic properties and is traditionally used in
religious ceremonies and initiation rites, but has also been claimed to
counter nicotine, cocaine and opiate addiction, via blockade of dopamine
release in the nucleus accumbens (and the dopamine response in general) in
chronic cocaine and opiate users
(Maisonneuve & Glick,
2003). Ibogaine also binds to the cocaine site of the serotonin
transporter (Staley et al,
1996), but its therapeutic value is limited as it is highly
neurotoxic and can cause irreversible cerebellar damage
(Maisonneuve & Glick,
2003); as a result, further clinical studies have been abandoned.
A synthetic derivative 18-methoxycoronaridine has similar reported effects but
no cerebellar toxicity or specific effects on the serotonin transporter
(Maisonneuve & Glick,
2003). To date 18-methoxycoronaridine has only been tested in
animal experiments where it has been shown to reduce cocaine, morphine and
alcohol intake in rats (Rezvani et
al, 1997; Glick et
al, 2000).
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Passion flower has also been used to ameliorate the effects of opiate, cannabis, benzodiazepine and nicotine addiction, but clinical data are limited (Dhawan et al, 2002a,b, 2003; Akhondzadeh et al, 2001b). Likewise, valerian has been tried in benzodiazepine withdrawal (Poyares et al, 2002) and St Johns wort has been used for the treatment of alcohol dependence (De Vry et al, 1999; Rezvani et al, 1999; Overstreet et al, 2003b), but effectiveness has not been established. Kudzu, Japanese arrowroot (Pueraria lobata), has traditionally been used for the treatment of alcoholic hangover. The active ingredient, purerarin, counteracts the anxiogenic effects associated with alcohol withdrawal (Overstreet et al, 2003a). Kudzu also contains two potent, reversible inhibitors of human alcohol dehydrogenase isozymes (Keung, 1993), but an effect has only been demonstrated in vitro (Lin & Li, 1998). One small trial among those with chronic alcohol misuse has not shown any difference from placebo (Shebek & Rindone, 2000). Further trials are required to test its genuine therapeutic potential, perhaps using more standardised formulations of the active ingredient.
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DISCUSSION |
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We have outlined only a limited range of complementary medicines used for the treatment of common psychiatric problems. Clearly there are many more remedies that may be taken to improve general health or to counter the side-effects of conventional treatments. Clinicians need to be aware of and enquire about such forms of self-medication, since all remedies may interact with prescribed medication or have associated side-effects in their own right. For instance, patients may take phyto-oestrogens, such as black colosh (Actaea racemosa), wild yam (Dioscorea composita) or dong quai (Angelica sinensis) to counter sexual side-effects, and this might pose a problem in patients with oestrogen receptor-positive breast cancer (Werneke et al, 2004a). For the same reason, patients may also try evening primrose oil (Oenothera biennis), which could decrease the effect of sodium valproate (Miller, 1989). Kelp (Laminaria digitata or Fucus vesiculosus) may be taken to counter weight gain, but can contain substantial amounts of iodine and can interfere with treatment for thyroid function disorders. Iodine taken together with lithium may have additive hypothyroid effects (Natural Medicines Comprehensive Database, 2004b).
Given the complex pattern of potential interactions, clinicians should not be afraid to discuss complementary medicines with their patients. Although some patients may choose to use complementary medicines as alternatives to conventional treatment, many may decide to use them in addition to prescribed medications. Complementary medicines have rightly or wrongly a very positive natural reputation among significant sections of the population, and therefore can be popular with those from a wide variety of cultural backgrounds. This may lead to higher acceptance and adherence compared with conventional drugs, making it important to be willing and prepared to work in partnership with patients beliefs and preferences provided their actions are safe (Brugha et al, 2004). Also, we do not know whether the agreed use of complementary medicines could in itself improve insight and subsequently lead to greater adherence to conventional treatment regimens. This emphasises the importance of further research on complementary medicines focusing on promising agents such as passion flower, valerian and S-adenosylmethionine, which appear to be obvious candidates for further RCTs. In addition, it might be important to consider patients attitudes and preferences in future studies, possibly targeting those demanding complementary medicines.
Finally, clinicians need to be aware of side-effects associated with complementary medicines and any interactions with other treatments. They should be able to identify hazards, advising patients accordingly and avoiding uncritical encouragement of potentially harmful use. Ignorance in this area, given the independent usage of complementary medicines, may lead to criticism and possibly litigation (Cohen & Eisenberg, 2002). Equally, patients should be encouraged to disclose information about complementary medicines to healthcare professionals. These discussions need to be conducted sensitively in order to avoid alienating patients who may feel that they have not been taken seriously or have been criticised for using complementary medicines. Such discussions can be complex and may demand more time than is available in routine clinics. Service models need to be designed to meet this challenge, with consideration being given to specialist clinics providing regular updated advice to both clinicians and patients.
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Clinical Implications and Limitations |
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LIMITATIONS
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ACKNOWLEDGMENTS |
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REFERENCES |
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Akhondzadeh, S., Naghavi, H. R., Vazirian, M., et al (2001a) Passionflower in the treatment of generalized anxiety: a pilot double-blind randomized controlled trial with oxazepam. Journal of Clinical Pharmacy and Therapeutics, 26, 363 367.[CrossRef][Medline]
Akhondzadeh, S., Kashani, L., Mobaseri, M., et al (2001b) Passionflower in the treatment of opiates withdrawal: a double-blind randomized controlled trial. Journal of Clinical Pharmacy and Therapeutics, 26, 369 373.[CrossRef][Medline]
Alderman, C. P. & Kiepfer, B. (2003)
Complementary medicine use by psychiatry patients of an Australian hospital.
Annals of Pharmacotherapy,
37, 1779
1784.
Amenta, F., Cavallotti, C., Franch, F., et al (1989) Muscarinic cholinergic receptors in the hippocampus of the aged rat: effects of long-term hydergine administration. Archives Internationales de Pharmacodynamie et de Thérapie, 297, 225 234.[Medline]
Benjamin, J., Muir, T., Briggs, K., et al
(2001) A case of cerebral haemorrhage can Ginkgo
biloba be implicated? Postgraduate Medical Journal,
77, 112
113.
Benton, D. (2002) Selenium intake, mood and other aspects of psychological functioning. Nutrition and Neurosciences, 5, 363 374.
Benton, D. Cook, R. (1991) Selenium supplementation improves mood in a double-blind crossover trial. Biological Psychiatry, 29, 1092 1098.[CrossRef][Medline]
Birks, J., Grimley Evans J. & Van Dongen, M. (2002) Gingko biloba for cognitive impairment and dementia. Cochrane Library, Issue 2. Oxford: Update Software.
Boerner, R. J., Sommer, H., Berger, W., et al (2003) Kava-Kava extract LI150 is as effective as opipramol and buspirone in generalised anxiety disorder an 8-week randomized, double-blind multi-centre clinical trial in 129 out-patients. Phytomedicine, 10 (suppl.), 3849.[Medline]
Bottiglieri, T., Laundy, M., Crellin, R., et al
(2000) Homocysteine, folate, methylation, and monoamine
metabolism in depression. Journal of Neurology, Neurosurgery and
Psychiatry, 69, 228
232.
Bowden, C. L. (2001) Novel treatments for bipolar disorder. Expert Opinion in Investigating Drugs, 10, 661 671.[CrossRef]
Bressa, G. M. (1994) S-adenosyl-1-methionine (SAMe) as antidepressant: meta-analysis of clinical studies. Acta Neurologica Scandinavica, 154 (suppl.), 714.
Brown, B. G., Zhao, X. Q., Chait, A., et al (2001) Simvastatin and niacin, antioxidant vitamins, or the combination for the prevention of coronary disease. New England Journal of Medicine, 29, 1583 1592.
Brugha, T., Rampes, H. & Jenkins, R. (2004)
Surely you take complementary and alternative medicines?
Psychiatric Bulletin,
28, 36
39.
Cardinali, D. P., Gvozdenovich, E., Kaplan, M. R., et al (2002) A double blind-placebo controlled study on melatonin efficacy to reduce anxiolytic benzodiazepine use in the elderly. Neuroendocrinology Letters, 23, 55 60.
Carman, J. S., Post, R. M., Buswell, R., et al (1976) Negative effects of melatonin on depression. American Journal of Psychiatry, 133, 1181 1186.[Abstract]
Chatterjee, S. S., Nolder, M., Koch, E., S. S., Nolder, M., Koch, E., et al (1998) Antidepressant activity of hypericum perforatum and hyperforin: the neglected possibility. Pharmacopsychiatry, 31 (suppl.), 715.[Medline]
Chevallier, A. (1996) The Encyclopedia of Medicinal Plants. London: Dorling Kindersley.
Coffin, A. I. (1845) Botanic Guide to Health and Natural Pathology of Diseases. London: J. Caudwell.
Cohen, M. H. & Eisenberg, D. M. (2002)
Potential physician malpractice liability associated with complementary and
integrative medicinal therapies. Annals of Internal
Medicine, 136, 596
603.
Committee on Safety of Medicines & Medicines Control Agency (2000) Reminder: St Johns wort (Hypericum perforatum) interactions. Current Problems in Pharmacovigilance, 26, 6 7.
Corrigan, J. J. Jr (1982) The effect of vitamin E on warfarin-induced vitamin K deficiency. Annals of the New York Academy of Sciences, 393, 361 368.[Abstract]
Cott, J.M. (1997) In vitro receptor binding and enzyme inhibition by hypericum perforatum extract. Pharmacopsychiatry, 30 (suppl.), 108112.[Medline]
De Vry, J., Maurel, S., Schreiber, R., et al (1999) Comparison of hypericum extracts with imipramine and fluoxetine in animal models of depression and alcoholism. European Neuropsychopharmacology, 9, 61 68.[CrossRef][Medline]
Delle Chiaie, R., Pancheri, P. & Scapicchio, P.
(2002) Efficacy and tolerability of oral and intramuscular
S-adenosyl-L-methionine 1,4-butanedisulfonate (SAMe) in the treatment of major
depression: comparison with imipramine in 2 multicenter studies.
American Journal of Clinical Nutrition,
76 (suppl.), 1172S
1176S.
Dhawan, K., Kumar, S. & Sharma, A. (2002a) Reversal of cannabinoids (delta9-THC) by the benzoflavone moiety from methanol extract of Passiflora incarnata Linnaeus in mice: a possible therapy for cannabinoid addiction. Journal of Pharmacy and Pharmacology, 54, 875 881.[CrossRef][Medline]
Dhawan, K., Kumar, S. & Sharma, A. (2002b) Nicotine reversal effects of the benzoflavone moiety from Passiflora incarnata Linneaus in mice. Addiction Biology, 7, 435 441.[CrossRef][Medline]
Dhawan, K., Dhawan, S. & Chhabra, S. (2003) Attenuation of benzodiazepine dependence in mice by a tri-substituted benzoflavone moiety of Passiflora incarnata Linneaus: a non-habit forming anxiolytic. Journal of Pharmacy and Pharmacological Science, 6, 215 222.
Diaper, A. & Hindmarch, I. (2004) Adouble-blind, placebo-controlled investigation of the effects of two doses of a valerian preparation on the sleep, cognitive and psychomotor function of sleep-disturbed older adults. Phytotherapy Research, 18, 831 836.[CrossRef][Medline]
Dinh, L. D., Simmen, U., Bueter, K. B., et al (2001) Interaction of various Piper methysticum cultivars with CNS receptors in vitro. Planta Medica, 67, 306 311.[CrossRef][Medline]
Dorn, M. (2000) Efficacy and tolerability of Baldrian versus oxazepam in non-organic and non-psychiatric insomniacs: a randomised, double blind, clinical comparative study. Forschende Komplementarmedizin und Klassische Naturheilkunde, 7, 79 84.[CrossRef][Medline]
Dravid, A. R. (1983) Deficits in cholinergic enzymes and muscarinic receptors in the hippocampus and striatum of senescent rats: effect of chronic hydergine treatment. Archives Internationales Pharmacodynamie et de Therapie, 264, 195 202.
Eisenberg, D. M., Kessler, R. C., Foster, C., et al
(1993) Unconventional medicine in the United States.
Prevalence, costs and pattern of use. New England Journal of
Medicine, 328, 246
252.
Ernst, E. (2002) "Flower remedies": a systematic review of the clinical evidence. Wiener Klinische Wochenschrift, 30, 963 966.
Ernst, E. & Cassileth, B. R. (1999) How useful are unconventional cancer treatments? European Journal of Cancer, 35, 1608 66.[Medline]
Fava, M., Giannelli, A., Rapisarda, V., et al (1995) Rapidity of onset of the antidepressant effect of parenteral S-adenosyl-L-methionine. Psychiatry Research, 56, 295 297.[CrossRef][Medline]
Fisher, A. A., Purcell, P. & Le Couteur, D. G. (2000) Toxicity of Passiflora incarnata L. Journal of Clinical Toxicology, 38, 63 66.
Food Standards Agency. Expert Group on Vitamins and Minerals (2003) Safe Upper Levels for Vitamins and Minerals. http://www.foodstandards.gov.uk
Friedel, H. A., Goa, K. L. & Benfield, P. (1989) S-adenosyl-L-methionine. A review of its pharmacological properties and therapeutic potential in liver dysfunction and affective disorders in relation to its physiological role in cell metabolism. Drugs, 38, 389 416.[Medline]
Fugh-Berman, A. (2000) Herbdrug interactions. Lancet, 355, 134 138.[CrossRef][Medline]
Glick, S. D., Maisonneuve, I. M. & Dickinson, H. A. (2000) 18-MC reduces methamphetamine and nicotine self-administration in rats. Neuroreport, 11, 2013 2015.[Medline]
Haag, M. (2003) Essential fatty acids and the brain. Canadian Journal of Psychiatry, 48, 195 203.[Medline]
Hamilton, M. (1967) Development of a rating scale for primary depressive illness. British Journal of Social and Clinical Psychology, 6, 278 296.
Hawkes, W. C. & Hornbostel, L. (1996) Effects of dietary selenium on mood in healthy men living in a metabolic research unit. Biological Psychiatry, 39, 121 128.[CrossRef][Medline]
Herxheimer, A. & Petrie, K. J. (2003) Melatonin for the prevention and treatment of jet lag. Cochrane Library, issue 4. Oxford: Update Software.
Houghton, P. J. (1999) The scientific basis for the reputed activity of Valerian. Journal of Pharmacy and Pharmacology, 51, 505 512.[CrossRef][Medline]
Itil, T. M., Ahmed, I., Kunitz, A., et al (1998) The pharmacological effects of ginkgo biloba, a plant extract, on the brain of dementia patients in comparison with tacrine. Psychopharmacology Bulletin, 34, 391 397.[Medline]
Jaroszewski, J.W., Olafsdottir, E. S., Wellendorph, P., et al (2002) Cyanohydrin glycosides of Passiflora: distribution pattern, a saturated cyclopentane derivative from P. guatemalensis, and formation of pseudocyanogenic alpha-hydroxyamides as isolation artifacts. Phytochemistry, 59, 501 511.[CrossRef][Medline]
Joy, C. B., Mumby-Croft, R. & Joy, L. A. (2003) Polyunsaturated fatty acid supplementation for schizophrenia. Cochrane Library, issue 4. Oxford: Update Software.
Jussofie, A., Schmiz, A. & Hiemke, C. (1994) Kavapyrone enriched extract from Piper methysticum as modulator of the GABA binding site in different regions of rat brain. Psychopharmacology, 116, 469 474.[CrossRef][Medline]
Kanowski, S. & Hoerr, R. (2003) Ginkgo biloba extract EGb 761 in dementia: intent-to-treat analyses of a 24-week, multi-center, double-blind, placebo-controlled, randomized trial. Pharmacopsychiatry, 36, 297 303.[CrossRef][Medline]
Kessler, R.C., Soukup, J., Davis, R. B., et al
(2001) The use of complementary and alternative therapies to
treat anxiety and depression in the United States. American Journal
of Psychiatry, 158, 289
294.
Keung, W. M. (1993) Biochemical studies of a new class of alcohol dehydrogenase inhibitors from Radix puerariae. Alcoholism, Clinical and Experimental Research, 17, 1254 1260.[Medline]
Klepser, T. B. & Klepser, M. E. (1999) Unsafe and potentially safe herbal therapies. American Journal of Health-System Pharmacy, 56, 125 138.
Knaudt, P. R., Connor, K. M., Weisler, R. H., et al (2001) Alternative therapy use by psychiatric outpatients. Journal of Nervous and Mental Disease, 187, 692 695.
Krasowski, M. D., McGehee, D. S. & Moss, J. (1997) Natural inhibitors of cholinesterases: implications for adverse drug reactions. Canadian Journal of Anaesthesia, 44, 525 534.[Medline]
Lee, B. M., Lee, S. K. & Kim, H. S. (1998) Inhibition of oxidative DNA damage, 8-OHdG, and carbonyl contents in smokers treated with antioxidants (vitamin E, vitamin C, beta-carotene and red ginseng). Cancer Letters, 132, 219 227.[CrossRef][Medline]
Lehrl, S. (2004) Clinical efficacy of kava extract WS 1490 in sleep disturbances associated with anxiety disorders. Results of a multicenter, randomized, placebo-controlled, double-blind clinical trial. Journal of Affective Disorders, 78, 101 110.[CrossRef][Medline]
Le Poncin-Lafitte, M., Rapin, J. R., Duterte, D., et al (1985) Learning and cholinergic neurotransmission in old animals: the effect of Hydergine. Pharmacology, 16 (suppl.), 57 63.[CrossRef]
Lewis, R., Wake, G., Court, G., et al (1999) Nonginsenoside nicotinic activity in ginseng species. Phytotherapy Research, 13, 59 64.[CrossRef][Medline]
Liede, K. E., Haukka, J. K., Saxen, L. M., et al (1998) Increased tendency towards gingival bleeding caused by joint effect of alpha-tocopherol supplementation and acetylsalicylic acid. Annals of Medicine, 30, 542 546.[Medline]
Lin, R. C. & Li, T. K. (1998) Effects of isoflavones on alcohol pharmacokinetics and alcohol-drinking behavior in rats. American Journal of Clinical Nutrition, 68 (suppl.), 1512S 1515S.[Abstract]
Linde, K., Ramirez, G., Mulrow, C. D., et al
(1996) St Johns wort for depression an
overview and meta-analysis of the randomised clinical trials.
BMJ, 313, 253
258.
Linde, K., Berner, M., Egger, M., et al
(2005) St Johns wort for depression. Meta-analysis of
randomised controlled trials. British Journal of
Psychiatry, 186, 99
107.
Lohr, J. B., Kuczenski, R. & Niculescu, A. B. (2003) Oxidative mechanisms and tardive dyskinesia. CNS Drugs, 17, 47 62.[CrossRef][Medline]
Maclennan, K. M., Darlington, C. L. & Smith, P. F. (2002) The CNS effects of Ginkgo biloba extracts and ginkgolide B. Progress in Neurobiology, 67, 235 257.[CrossRef][Medline]
MacMahon, K. M. A., Broomfield, N. M. & Espie, C. A. (2005) A systematic review of the effectiveness of oral melatonin for adults (18 to 65 years) with delayed sleep phase syndrome and adults (18 to 65 years) with primary insomnia. Current Psychology Reviews, 1, 103 113.[CrossRef]
Maisonneuve, I. M. & Glick, S. D. (2003) Antiaddictive actions of an iboga alkaloid congener: a novel mechanism for a novel treatment. Pharmacology, Biochemistry and Behavior, 75, 607 618.[CrossRef][Medline]
Malamud, W., Barton, W. E., Fleming, A. M., et al
(1957) The evaluation of the effects of derivatives of
Rauwolfia in the treatment of schizophrenia. American Journal of
Psychiatry, 114, 193
200.
Marangell, L. B., Martinez, J. M., Zboyan, H. A., et al
(2003) A double-blind, placebo-controlled study of the
omega-3 fatty acid docosahexaenoic acid in the treatment of major depression.
American Journal of Psychiatry,
160, 996
998.
Markstein, R. (1985) Hydergine: interaction with the neurotransmitter systems in the central nervous system. Journal of Pharmacology, 16 (suppl.), 1 17.
Mash, D. C., Staley, J. K., Pablo, J. P., et al (1995) Properties of ibogaine and its principal metabolite (12-hydroxyibogamine) at the MK-801 binding site of the NMDA receptor complex. Neuroscience Letters, 192, 53 56.[CrossRef][Medline]
Mathews, J. M., Etheridge, A. S. & Black, S. R.
(2002) Inhibition of human cytochrome P450 activities by kava
extract and kavalactones. Drug Metabolism and
Disposition, 30, 1153
1157.
Matthews, M. K. Jr (1998) Association of Ginkgo biloba with intracerebral hemorrhage. Neurology, 50, 1933 1934.[Medline]
Matthews, S. C., Camacho, A., Lawson, K., et al (2003) Use of herbal medications among 200 psychiatric outpatients: prevalence, patterns of use, and potential dangers. General Hospital Psychiatry, 25, 24 26.[CrossRef][Medline]
Medical Economics (2000) PDR (Physicians Desk Reference) for Herbal Medicines (2nd edn). Montvale, NJ: Medical Economics Company.
Meseguer, E., Taboada, R., Sanchez, V., et al (2002) Life-threatening parkinsonism induced by kava-kava. Movement Disorders, 17, 195 196.[CrossRef][Medline]
Miller, L. G. (1989) Herbal medicinals: selected clinical considerations focusing on known or potential drugherb interactions. Archives of Internal Medicine, 158, 2200 2211.
Mischoulon, D. & Fava, M. (2002) Role of
S-adenosyl-L-methionine in the treatment of depression: a review of the
evidence. American Journal of Clinical Nutrition,
76 (suppl.), 1158S
1161S.
Morris, M., Fava, M. & Jaques, P. F. (2003) Depression and folate status in the US population. Psychotherapie Psychosomatik, 72, 80 87.
Müller, W. E., Singer, A., Wonnemann, M., et al (1998) Hyperforin represents the neurotransmitter reuptake inhibiting constituent of hypericum extract. Pharmacopsychiatry, 31 (suppl.), 1621.[Medline]
Munoz-Hoyos, A., Sanchez-Forte, M., Molina-Carballo, A., et al (1998) Melatonins role as an anticonvulsant and neuronal protector: experimental and clinical evidence. Journal of Child Neurology, 13, 501 509.[Medline]
Natural Medicines Comprehensive Database (2004a) http://www.naturaldatabase.com. Product search:Kava.
Natural Medicines Comprehensive Database (2004b) http://www.naturaldatabase.com. Product search: Iodine.
Natural Medicines Comprehensive Database (2004c) http://www.naturaldatabase.com. Product search: Selenium.
Natural Medicines Comprehensive Database (2004d) http://www.naturaldatabase.com. Product search: Folic acid.
Natural Medicines Comprehensive Database (2004e) http://www.naturaldatabase.com. Product search: Indian snakeroot.
Natural Medicines Comprehensive Database (2004f) http://www.naturaldatabase.com. Product search:Iboga.
Natural Medicines Comprehensive Database (2004g) http://www.naturaldatabase.com. Product search:Kudzu.
Neary, J. T. & Bu, Y. (1999) Hyperforin inhibits uptake of serotonin and norepinephrine in astrocytes. Brain Research, 816, 358 363.[CrossRef][Medline]
Nemets, B., Stahl, Z. & Belmaker, R. H.
(2002) Addition of omega-3 fatty acid to maintenance
medication treatment for recurrent unipolar depressive disorder.
American Journal of Psychiatry,
159, 477
479.
Oken, B. S., Storzbach, D. M. & Kaye, J. A.
(1998) The efficacy of ginkgo biloba on cognitive function in
Alzheimer disease. Archives of Neurology,
55, 1409
1415.
Olde Rikkert, M. G. & Rigaud, A. S. (2001) Melatonin in elderly patients with insomnia. A systematic review. Gerontology and Geriatrics, 34, 491 497.
Olin, J., Schneider, L., Novit, A., et al (2001) Hydergine for dementia. Cochrane Library, issue 4. Oxford: Update Software.
Ondrizek, R. R., Chan, P. J., Patton, W. C., et al (1999) Inhibition of human sperm motility by specific herbs used in alternative medicine. Journal of Assisted Reproduction and Genetics, 16, 87 91.[CrossRef][Medline]
Overstreet, D. H., Keung, W. M., Rezvani, A. H., et al (2003a) Herbal remedies for alcoholism: promises and possible pitfalls. Alcoholism, Clinical and Experimental Research, 27, 177 185.[CrossRef][Medline]
Overstreet, D. H., Kralic, J. E., Morrow, A. L., et al (2003b) NPI-031G (puerarin) reduces anxiogenic effects of alcohol withdrawal or benzodiazepine inverse or 5-HT(2C) agonists. Pharmacology, Biochemistry and Behavior, 75, 619 625.[CrossRef][Medline]
Pancheri, P., Scapicchio, P. & Chiaie, R. D. (2002) A double-blind, randomized parallel-group, efficacy and safety study of intramuscular S-adenosyl-L-methionine 1,4-butanedisulphonate (SAMe) versus imipramine in patients with major depressive disorder. International Journal of Neuropsychopharmacology, 5, 287 294.[Medline]
Perovic, S. & Müller, W. E. (1995) Pharmacological profile of hypericin extract. Effect on serotonin reuptake by postsynaptic receptors. Arzneimittelforschung, 45, 1145 1148.[Medline]
Pittler, M. H. & Ernst, E. (2003) Kava extract for treating anxiety. Cochrane Library, issue 4. Oxford: Update Software.
Poyares, D. R., Guilleminault, C., Ohayon, M. M., et al (2002) Can valerian improve the sleep of insomniacs after benzodiazepine withdrawal? Progress in Neuropsychopharmacology and Biological Psychiatry, 26, 539 545.[CrossRef][Medline]
Rezvani, A. H., Overstreet, D. H., Yang, Y., et al (1997) Attenuation of alcohol consumption by a novel nontoxic ibogaine analogue (18-methoxycoronaridine) in alcohol-preferring rats. Pharmacology, Biochemistry and Behavior, 58, 615 619.[CrossRef][Medline]
Rezvani, A. H., Overstreet, D. H., Yang, Y., et al
(1999) Attenuation of alcohol intake by extract of Hypericum
perforatum (St. Johns Wort) in two different strains of
alcohol-preferring rats. Alcohol and Alcoholism,
34, 699
705.
Rezvani, A. H., Overstreet, D. H., Perfumi, M., et al (2003) Plant derivatives in the treatment of alcohol dependency. Pharmacology, Biochemistry and Behavior, 75, 593 606.[CrossRef][Medline]
Roberts, C. G. & Ladenson, P.W. (2004) Hypothyroidism. Lancet, 363, 793 803.[CrossRef][Medline]
Roder, C., Schaefer, M. & Leucht, S. (2004) Meta-analysis of effectiveness and tolerability of treatment of mild to moderate depression with St. Johns Wort. Fortschritte der Neurologie Psychiatrie, 72, 330 343.[CrossRef][Medline]
Sano, M., Ernesto, C., Thomas, R. G., et al
(1997) A controlled trial of selegeline, alpha-tocopherol or
both as treatment for Alzheimers disease. New England
Journal of Medicine, 336, 1216
1222.
Schelosky, L., Raffauf, C. & Jendroska, K. (1995) Kava and dopamine antagonism. Journal of Neurology, Neurosurgery and Psychiatry, 58, 639 640.[Medline]
Schmitz, M. & Jackel, M. (1998) Comparative study for assessing quality of life of patients with exogenous sleep disorders (temporary sleep onset and sleep interruption disorders) treated with a hops-valerian preparation and a benzodiazepine drug. Wiener Medizinische Wochenschrift, 148, 291 298.[Medline]
Schreiter-Gasser, U. & Gasser, T. (2001) A comparison of cholinesterase inhibitors and ginkgo extract in treatment of Alzheimer dementia. Fortschritte der Medizin Originalien, 119, 135 136.[Medline]
Shamir, E., Barak, Y., Plopsky, I., et al (2000) Is melatonin treatment effective for tardive dyskinesia? Journal of Clinical Psychiatry, 61, 556 558.[Medline]
Shamir, E., Barak, Y. & Shalman, I. (2001)
Melatonin treatment for tardive dyskinesia: double-blind, placebo-controlled,
crossover study. Archives of General Psychiatry,
58, 1049
1052.
Shebek, J. & Rindone, J. P. (2000) A pilot study exploring the effect of kudzu root on the drinking habits of patients with chronic alcoholism. Journal of Alternative and Complementary Medicine, 6, 45 48.[Medline]
Sheppard, S. G. (1994) A preliminary investigation of ibogaine: case reports and recommendations for further study. Journal of Substance Abuse and Treatment, 11, 379 385.
Sher, L. (2001) Role of thyroid hormones in the effects of selenium on mood, behavior, and cognitive function. Medical Hypotheses, 57, 480 483.[CrossRef][Medline]
Singer, C., Tractenberg, R. E., Kaye, J., et al (2003) Alzheimers Disease Cooperative Study. A multicenter, placebo-controlled trial of melatonin for sleep disturbance in Alzheimers disease. Sleep, 26, 893 901.[Medline]
Soares, K. V. S. & McGrath, J. J. (2001) Vitamin E for neuroleptic-induced tardive dyskinesia. Cochrane Library, issue 4. Oxford: Update Software.
Spinella, M. (2001) Psychotherapeutic herbs. In The Psychopharmacology of Herbal Medicine, p. 278 . Cambridge, MA: MIT Press.
Staley, J. K., Ouyang, Q. & Pablo, J. (1996) Pharmacological screen for activities of 12-hydroxyibogamine: a primary metabolite of the indole alkaloid ibogaine. Psychopharmacology, 127, 10 18.[Medline]
Stevinson, C. & Ernst, E. (2000) Valerian for insomnia: a systematic review of randomized clinical trials. Sleep Medicine, 1, 91 99.[CrossRef][Medline]
Stoll, A. L., Severus, W. E., Freeman, M. P., et al
(1999) Omega 3 fatty acids in bipolar disorder: a preliminary
double-blind, placebo-controlled trial. Archives of General
Psychiatry, 56, 407
412.
Su, K. P., Huang, S.Y., Chiu, C. C., et al (2003) Omega-3 fatty acids in major depressive disorder. A preliminary double-blind, placebo-controlled trial. European Neuropsychopharmacology, 13, 267 271.[CrossRef][Medline]
Szegedi, A., Kohnen, R., Dienel, A., et al
(2005) Acute treatment of moderate to severe depression with
hypericum extract WS5570 (St Johns wort): randomised controlled double
blind non-inferiority trial against paroxetine. BMJ,
330, 503
506.
Tabet, N., Birks, J. & Grimley Evans J. (2000) Vitamin E for Alzheimers disease. Cochrane Library, issue 4. Oxford: Update Software.
Tang, F., Nag, S., Shiu, S.Y., et al (2002) The effects of melatonin and Ginkgo biloba extract on memory loss and choline acetyltransferase activities in the brain of rats infused intracerebroventricularly with beta-amyloid. Life Sciences, 71, 2625 2631.[CrossRef][Medline]
Taylor, M. J., Carney, S., Geddes, J., et al (2004) Folate for depressive disorders. Cochrane Library, issue 1. Oxford: Update Software.
Teufel-Mayer, R. & Gleitz, J. (1997) Effect of long term administration of hypericin extracts on the affinity and density of the central serotonergic 5HT1A and 5HT2A receptors. Pharmacopsychiatry, 30 (suppl. 2), 113116.[Medline]
Thiele, B., Brink, I. & Ploch, M. (1994)
Modulation of cytokine expression by hypericin extract. Journal of
Geriatric Psychiatry and Neurology,
7 (suppl. 1), S60
S62.
Tian, J. Z., Zhu, A. H. & Zhong, J. (2003) A follow-up study on a randomized, single-blind control of Kings Brain pills in treatment of memory disorder in elderly people with MCI in a Beijing community. Zhongguo Zhong Yao Za Zhi, 28, 987 991.[Medline]
Unutzer, J., Klap, R., Sturm, R., et al
(2000) Mental disorders and the use of alternative medicine:
results from a national survey. American Journal of
Psychiatry, 157, 1851
1857.
van Dongen, M., van Rossum, E., Kessels, A., et al (2003) Ginkgo for elderly people with dementia and age-associated memory impairment: a randomized clinical trial. Clinical Epidemiology, 56, 367 376.
Viola, H., Wasowski, C. & Levi de Stein, M. (1995) Apigenin, a component of Matricaria recutita flowers, is a central benzodiazepine receptors-ligand with anxiolytic effects. Planta Medica, 61, 213 216.[Medline]
Vogeler, B. K., Pittler, M. H. & Ernst, E. (1999) The efficacy of ginseng. A systematic review of randomized controlled trials. European Journal of Clinical Pharmacology, 55, 567 575.[CrossRef][Medline]
Wang, J. L., Patten, S. B. & Russell, M. L. (2001) Alternative medicine use by individuals with major depression. Canadian Journal of Psychiatry, 46, 528 533.[Medline]
Watanabe, H., Kakihana, M., Ohtsuka, S., et al (1997) Randomized, double-blind, placebo-controlled study of supplemental vitamin E on attenuation of the development of nitrate tolerance. Circulation, 96, 2545 2550.