sign in sign up
<<
Home , Valerian (herb)

BRITISH JOURNAL OF PSYCHIATRY (2006), 188, 109-121 REVIEW ARTICLE

Complementary medicines in psychiatry medicines have fewer or no side-effects,and many with chronic anxiety and depression understandably feel disillusioned by the ap- Review of effectiveness and safety parent ineffectivenessof conventional treat- ment. The aim of this review is to acquaint URSULA WERNEKE, TREVOR TURNER and STEFAN PRIEBE psychiatrists with the complementary med- icines routinely encountered in clinical practice, to review the evidence base for '. their purported effectivenessand to discuss potential adverse effects and interactions.

METHOD Background The use of Complementary medicines are either used as an alternative or in addition to conven- We searched the Medline and Cochrane complementary medicines inthose with tional medicine (Zimmerman & Thomp- databases for evidence of the effectiveness mental health problems iswell son, 2002). Their use by those with of complementary medicines for the treat- documented. However, their effectiveness chronic disorders such as cancers, with ment of psychiatric conditions. We divided is often not established and they may be their associated physical and psychological the substances into different categories: less harmless than commonly assumed. problems, is well documented (Eisenberg cognitive enhancers, and anxioly- et ai, 1993; Ernst & Cassileth, 1999). In tics, , and Aims To review the complementary psychiatric patients, estimates of their use remedies for movement disorders, and medicines routinely encountered in range from 8 to 57%, with the most fre- anti-addictives. Search terms included the psychiatric practice, their effectiveness, quent use being in depression and anxiety. identified substances in each category and A population-based study from the USA EFFECTIVENESS or SIDE-EFFECTS or potential adverse effects and interactions. found that 9% of respondents had anxiety ADVERSE DRUG REACTION or Method Electronic and manual attacks, 57% of whom used complemen- INTERACTION. All recovered papers tary medicines; 7% of respondents reported were reviewed for further relevant literature search on the effectiveness and severe depression, with 54% of these using references. All evidence was collated and safety of psychotropic complementary complementary medicines (Kessler et ai, ranked as available. We also accessed medicines. 2001). Another survey from the USA re- web-based resources, such as the Natural ported mental disorders in 14% of respon- Medicines Comprehensive Database Results Potentially usefulsubstances dents, 21% of whom used complementary (http://www.naturaldatabase.com). and for include and hydergine as cognitive medicines (Unutzer et ai, 2000). Usage mularies, such as the PDR (Physicians' enhancers, passion flower and valerian as was highest (32%) in respondents with Desk Reference for Medicines; panic disorder. In studies restricted to those Medical Economics, 2000) for further in- sedatives, StJohn'swort and s- with psychiatric disorders, usage ranged formation on the identified substances. adenosylmethionine as antidepressants, from 13 to 54% (Knaudt et ai, 2001; Wang Where available, we used reviews summar- and selenium and folate to complement et aI, 2001; Alderman & Kiepfer, 2003; ising the proposed mechanism of action and antidepressants. The evidence is less Matthews et aI, 2003). Complementary effectiveness, since presenting all the evi- medicines are also used by those seen by dence in detail was beyond the scope of this conclusive for the use ofomega-3 fatty liaison psychiatrists and a recent study of paper. Whenever possible, we gave priority acids as augmentation treatment in cancer patients showed that 25% took to meta-analyses, systematic reviews and schizophrenia, for tardive substances with psychoactive properties double-blind randomised controlled trials dyskinesia and 18-methoxycoronaridine, (Werneke et aI, 2004a). (RCTs), but we also included other evi- an ibogaine derivative, for the treatment Complementary medicines can be dence such as open trials and case reports of cocaine and heroin addiction. grouped into herbal remedies, food supple- when the findings were relevant to our ments, including vitamin preparations, and review. Where standardised comparative Conclusions Systematic clinicaltrials other organic and inorganic substances, in- measures such as the Hamilton Rating cluding omega-3 fatty acids. Some people Scale for Depression (HRSD; Hamilton, are needed to test promising substances. take food supplements and vitamin pre- 1967) were available for meta-analyses, Meanwhile, those wishing to take parations in high doses, often outside the we reported the relevant risk ratios. Owing psychotropic complementary medicines safety margins recommended by the Food to the heterogeneity of the data, no attempt require appropriate advice. Standards Agency (Food Standards Agency, at meta-analysis of other trials was made. 2003). People with mental health problems We included only studies applicable to gen- Declaration of interest None. may take complementary medicines to treat eral adult psychiatry and psychiatry of old- anxiety and depression or to counter side- er adults. Other special patient groups and effects of conventional treatments, for ex- healthy volunteers were excluded, as were ample tardive dyskinesia and weight gain. studies on a combination of substances Some seek a more holistic approach to with evidence available for the single treatment, others hope that complementary substance (Fig. 1).

109 WERNEKE ET AL

RESULTS Cognitive enhancers 296 Anxiolyticsand sedatives 227 Two thousand and seven studies were identi- Papers and documents possibly eligible 2007 Antidepressants and augmentation 1165 fied for the 20 remedies under review for the Antipsychotics,augmentation and five categories of mental health problems. treatments for tardive dyskinesia 100 Excluded 1963 The literature ranged from case reports and Anti-addictives 43 narrative reviews to systematic reviews in- Exclusion criteria: - higher ranking evidence cluding meta-analyses. For four categories, available; the evidence with regard to efficacy could combinations of substances; be limited to RCTs, systematic revie;.ys and special patient groups; meta-analyses. For anti-addictive substances healthy volunteer swdies we also considered open trials, since there was very lirtle evidence available (Fig. 1). Studies included 44 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 Cognitive and Antidepressants and Antipsychotics, Anti-addictives 4 increasing choline availability in the brain, enhancers 8 sedatives 8 augmentation 15 augmentation and treatments RCTs 2 e.g. by inhibiting acetylcholinesterase. SRs/MAs 4 SRs/MAs 3 SRs/MAs 8 for tardive OTRs 2 Alternative non-cholinergic neuroprotec- RCTs 4 RCTs 5 RCTs 7 dyskinesia 7 tive strategies have been postulated; these SRslMAs 2 include antioxidants scavenging free radi- RCTs 5 cals, thereby reducing neurotoxicity, and anticoagulants increasing cerebral blood Fig. I Selection of efficacy studies. SRs.systematic reviews; MAs. meta-analyses; RCTs. randomised flow (Spinella, 2001). Suggested herbal controlled trials; OTRs. open trials. cognitive enhancers include ginkgo, gin- seng, hydergine, which is an ergot (Clavi- ceps purpurea) derivative, and solanceous Anxiolytics and sedatives has an effect that has been , including potatoes, tomatoes and established in several RCTs (pittler & aubergines (Table 1). Anxiolytics and sedatives essentially have Ernst, 2003). Kava has been associated Although in some individuals with the same underlying mechanisms of action. with several cases of liver toxicity (Natural Alzheimer's disease has been The stronger the agent the greater the seda- Medicines Database, 2004a), which has led reported to improve cognitive performance tive effect, leading to coma in extreme to its voluntary withdrawal from the UK (Birks et ai, 2002; Kanowski & Hoerr, cases. Four mechanisms of action have been market. Valerian ( or 2003), another trial did not show any ben- implicated (Spinella, 2001): (a) binding to Valeriana edulis) is a believed to efit in elderly people with Alzheimer's dis- gamma-aminobutyric acid (GABA) recep- have been known to and Dioscorides, ease of vascular type or age-associated tors leading to hyperpolarisation of the cell which has maintained its importance cognitive impairment (van Dongen et ai, membrane through increased influx of throughout the centuries (Spinella, 2001). 2003). Whether the effect in those with Alz- cWorine anions; (b) inhibition of excitatory In 1845, Coffin described it as 'an excellent heimer's disease is equivalent to that of syn- amino acids, thereby also impairing the sedative. . .predisposing the mind to quiet- thetic cholinesterase inhibitors is debatable ability to form new memories; (c) sodium ness and the body to sleep'. Valerian may (hil et ai, 1998; Wettstein, 2000; Schreiter- channel blockade, decreasing depolarisa- have comparable efficacy to Gasser & Gasser, 2001). Hydergine tion of the cell membrane; and (d) (Dorn, 2000; Ziegler et ai, 2002). However, was reported to lead to significant improve- channel blockade, decreasing the release a systematic review on the effectivenessof ment of cognitive impairment in dementia, of into the synaptic valerian in produced inconclusive but most studies were performed before cleft. Most complementary medicines results (Stevinson& Ernst, 2000). standardised dementia criteria were agreed prescribed for anxiolysis/sedation (e.g. kava Passion flower ( incamata) (Olin et ai, 2001). The results for panax kava, valerian, passion flower and contains chrysin, a partial to benzo- and vitamin E were inconclusive ) are GABAergic, though for diazepine receptors. One study comparing (Sano et ai, 1997; Vogeler et ai, 1999). some such as the mechanism of action passion flower with oxazepam found both Solanaceous plants may exercise strong remains unknown. As expected, all rem- to be equally effective (Akhondzadeh et cholinergic effects by inhibiting not only edies can lead to drowsiness when taken ai, 2001a); more trials are needed to acetyl- but also butyrylcholinesterase. in high doses and can potentiate the effect confirm the effect. No data are available However, no clinical studies have been con- of synthetic sedatives (Table 2). on chamomile and hops. Chamomile ducted to determine their effects on cogni- The most researched substance is kava (Chamaemelum nobile or Matricaria tion. They may augment cocaine toxicity kava (Pipermethysticum), which originated recutita) contains which binds to via the same mechanism (Krasowski et ai, from Polynesia and was traditionally used receptors (Viola et ai, 1997). for religious rituals (Chevallier, 1996). 1995). The mechanism of action for hops

110 Table I Cognitive enhancers

Substance Postulated mechanism of action Effectiveness Side-effects Potential drug interactions

Ginkgo Antioxidant: destroying free radicals Possible improvement of cognitive function, t Bleeding time. Case reports of Antithrombolytic agents (Medical implicated in cell damage (Oken et aI, 1998; activities of daily living and mood in those intracerebral haemorrhage Economics, 2000) Tabet et 01,2000); t cerebral blood flow with Alzheimer's disease or other cognitive (Matthews, 1998; Benjamin et 01, 2001); through platelet activation factor inhibition decline, but recent results inconsistent (Birks possibly adverse effects on male and and pathways (Maclennan et aI, etal, 2002; Kanowski & Hoerr, 2003; van female fertility (Ondrizek et al. 1999) 2002; Ahlemeyer & Krieglstein, 2003); Dongen etal, 2003) cholinergic effects (Tang etal. 2002) Panax ginseng Interference with platelet aggregation and Improvement of mental arithmetic and Insomnia, mania, hyper- and hypo- Insulin and oral hyperglycaemics, anti- coagulation (Medical Economics, 2000); abstraction; age-delaying properties tension, t vaginal bleeding (Medical thrombombolytic agents, MAOls neuroprotection through nicotinic activity unproven (Vogeler et al. 1999); one Economics, 2000) (). loop diuretics (Medical (Lewis et aI, 1999). antioxidant effects (Lee recent trial reporting marginal improvement Economics. 2000) et aI, 1998) in Mini-Mental State Examination and improvement in memory tests (Tian etal. 2003) Hydergine t Cholinergic activity (Le Poncin-Lafitte Significant improvement in dementia patients; Cholinergic and monoaminergic Serotonergic antidepressants, () et aI, 1985); reversal of age-related decline of hydergine was more effective at higher doses side-effects possible; risk of cholinesterase inhibitors choline acetyltransferase (Dravid, 1983) and and in younger patients (Olin et 01,200 I) psychotic recurrence muscarinic receptors (Amenta et aI, 1989); modulation of all monoaminergic neuro- transmitter systems (Markstein, 1985) Vitamin E Antioxidant (Tabet et aI, 2000) Behavioural but no cognitive improvement High doses: t risk of bleeding due to Anticoagulants including aspirin, clodipro- n with combination of vitamin E with selegiline; antagonism of vitamin K-dependent gel, warfarin (Corrigan, 1982; Liedeetal, o possibly delay of residential care using vitamin E clotting factors (Liede et aI, 1998) 1998) and herbal anticoagulants such as ~ ...." m (Sanoetal,1997) ginkgo, garlic and ginseng; possible preven- ~ m tion of nitrate tolerance (Watanabe et aI, Z -I » 1997); possible t effect of sildenafil and .. -< related phosphodiesterase-5 inhibitors ~ m Solanaceous plants Inhibit acetylcholinesterase and No study available Cholinergic poisoning through Prolonged action of pancuronium, other C butyrylcholinesterase (Krasowski dietary intake possible myorelaxants and cocaine through t n z m et aI, 1997) (Krasowski et al. 1997) inhibition of butyrylcholinesterase III (Krasowski etal, 1997) Z ." III MAOls, monoamine oxidase inhibitors. -< n J: » -I .. -< WERNEKE ET AL

(Humulus lupulus) remains unclear. Bach However, four of these meta-analyses have psychosis.Rauwolfia (Rauwolfia serpentina) flower remedies are a combination of 38 demonstrated equivalence to standard anti- extracts were traditionally used before flowers and seem to have no effect (Ernst, depressants (Linde et aI, 1996; Whiskey et synthetic antipsychotics became widely 2002). Melatonin extracted from the pineal aI, 2001; Roder et aI, 2004; Linde et aI, available, several derivatives, in- gland may improve sleep in those with 2005). One recent trial using high doses cluding reserpine, being introduced in the delayed sleep phase disorder, but no benefit (up to 1800 mg) of St John's wort reported 1950s (Malamud et aI, 1957). Rauwolfia has been shown in the treatment of primary equivalence to in those with originates from India and was mentioned sleep disorder (MacMahon et aI, 2005). It moderate or severe depression (Szegedi et in Ayurvedic medicine around 700 BC(Che- may also improve initial sleep quality in aI, 2005). Hyperforin, which inhibits the vallier, 1996). It blocks vesicular storage of older adults with insomnia (Olde Rikkert reuptake of monoamines, is thought to monoamines, allowing them to be more & Rigaud, 2001), but its role as a treatment be the most likely active component easily degraded by monoamine oxidases in for insomnia in those with Alzheimer's dis- (Chatterjee et aI, 1998; Miiller et aI, the cytoplasm. As a consequence, the ease remains disputed (Cardinali et aI, 1998). Thus, the use of extracts with amount of available on 2002; Singer et aI, 2003). maximum hyperforin content should be depolarisation of the cell membrane is re- examined more systematically (Werneke duced (Spinella, 2001), which may lead to et aI, 2004b). a reduction in and the resolution Antidepressants Folate and S-adenosylmethionine are in of psychotic symptoms. However, and augmentation therapy the same biochemical pathway, with folate and noradrenaline will also be less avail- All known synthetic antidepressants act via being required to synthesise methionine, the able, which explains why reserpine readily the enhancement of serotonergic and nora- direct precursor of S-adenosylmethionine, precipitates depression. An alternative drenergic neurotransmission. Most comple- from homocysteine. S-adenosylmethionine strategy is the augmentation of anti- mentary antidepressants are thought to facilitates many methylation reactions psychotic treatment with omega-3 fatty work through the same pathways (Tables required for the synthesis of many neuro- acids, but the results of clinical trials remain 3 and 4). The mechanism of action for sele- transmitters (Bottiglieri et aI, 2000; Morris inconclusive (Joy et aI, 2003; Table 5). nium is not clear but does seem to be differ- et aI, 2003). Thus, those with high levels Attempts have been made to treat tard- ent. Its antioxidant qualities may reduce of homocysteine may be more likely to ive dyskinesia with vitamin E. This treat- nerve cell damage (Benton, 2002), and it become depressed, or possibly less likely ment strategy relies on the assumption is also known to facilitate conversion from to respond to treatment. that tardive dyskinesia not only results thyroxine (T4) to thyronine (T3); T3 substi- Interestingly, hypothyroidism can lead to from dopamine supersensitivity tution is one possible means of augmenta- an increase in homocysteine levels (Roberts but is also related to the oxidative tissue tion of antidepressants in conventional & Ladenson, 2004) and this may contri- damage of drugs (Shamir et psychiatry. There are no clinical studies bute to the associated depression. In clinical aI, 2001; Lohr et aI, 2003). Meta-analysis but low selenium levels have been asso- studies, folate has been reported to be effec- of ten small trials has indicated that vitamin ciated with depression, anxiety and hosti- tive only when added to antidepressant E protects against deterioration of tardive lity (Hawkes & Hornbostel, 1996), and therapy (Taylor et aI, 2004). dyskinesia (Soares & McGrath, 2001); high dietary intake or supplementation Parenteral S-adenosylmethionine has one recent trial has reported improvement has been associated with mood improve- been reported to be superior to placebo (Zhang et aI, 2004). A far more powerful ment. The apparent therapeutic effect may (Bressa, 1994), and equivalence to imipra- antioxidant than vitamin E is melatonin, be dose-dependent (Benton & Cook, 1991; mine has been demonstrated in two RCTs which attenuates the dopaminergic activity Benton, 2002). Like lithium, there may be (Delle Chiaie et aI, 2002; Pancheri et aI, in the striatum as well as the release of a narrow therapeutic index. A recent report 2002). The onset of action may be more dopamine from the hypothalamus (Shamir by the Food Standards Agency (2003) re- rapid (Fava et aI, 1995). Oral S-adenosyl- et aI, 2001; Lohr et aI, 2003). However, duced the recommended limits of safe daily methionine may require doses four times as with omega-3 fatty acids, clinical trials intake. Trials may be most promising in as high as the parenteral formulation (Delle have been inconclusive (Shamir et aI, those with a low baseline selenium level. Chiaie et aI, 2002). Finally, omega-3 fatty 2000, 2001), and larger trials are required The most robust clinical data are acids are known to stabilise membranes to test its therapeutic effectiveness(Table 5). available for St John's wort (Hypericum and to facilitate monoaminergic, serotoner- Anti-addictives perforatum). These have been extensively gic and cholinergic neurotransmission reviewed in meta-analyses (Linde et aI, (Haag, 2003) but their antidepressant effect Although there are many addictive plants, 1996; Williams et aI, 2000; Whiskey et has not been convincingly demonstrated in few have been identified as having the aI, 2001; Roder et aI, 2004; Werneke et clinical studies (Marangell et aI, 2003; Su potential to counter addiction (Table 6). aI, 2004b; Linde et aI, 2005; Table 3) which et aI, 2003). Omega-3 fatty acids are poss- Such may be ibogaine, which is derived have found a decrease in effect size over ibly effective when added to lithium in the from the West African shrub Tabemanthe time when tested against placebo. The more treatment of bipolar affective disorder iboga. It has hallucinogenic properties and recent meta-analyses mostly suggest that (Bowden, 2001; Table 4). is traditionally used in religious ceremonies the effectivenessof StJohn's wort is limited and initiation rites, but has also been to mild depression, and more homogenous Antipsychotics, augmentation claimed to counter nicotine, cocaine and studies targeting patients with mild and treatment of tardive dyskinesia opiate addiction, via blockade of dopamine depression are required (Roder et aI, 2004; Only two complementary medicines have release in the nucleus accumbens (and the Werneke et aI, 2004b; Linde et aI, 2005). been suggested for the treatment of dopamine response in general) in chronic

112 Table 2 Anxiolytics and sedatives

Substance Postulated mechanism of action Effectiveness Side-effects Potential drug interactions

Valerian GABAergic effects (Houghton. 1999) Inconclusive evidence. May improve sleep Cognitive impairment and drowsiness; case i Effect of sedatives. CYPA4 inhibitor (see latency and slow wave sleep (Stevinson & reports of (Klepser & Table 3) Ernst. 2000); no more effective than placebo Klepser. 1999) in patients with acute sleep problems (Diaper & Hindmarch. 2004); comparable efficacy to oxazepam in patients with non-organic insomnia (Dorn. 2000; Ziegler et al. 2002)

Passion flower to benzodiazepine Comparable efficacy to oxazepam in treat- Case report of severe nausea. vomiting. Anticoagulants. i effect of sedatives. CYP3A4 receptors (Wolfman et al. 1994) ment of general drowsiness. prolonged QTc and episodes of inhibitor (see Table 3) (Akhondzadeh et al. 2001a) non-sustained ventricular tachycardia (Fisher et al. 2000); may contain cyanogenic glyco- sides (Jaroszewski et al. 2002)

Kava GABAergic effects (Jussofie et al. 1994; Meta-analysis of nine studies showed At least 68 cases of liver toxicity (NMCD. CYPIA2. 2C9. 2C19. 2D6. 3A4 and 4A9/11 Dinh et al. 200 I). D2 antagonist significant reduction of HRSA score 20040); one case report of movement inhibition (Mathews et al. 2002) (Schelosky et al. 1995) compared with placebo (weighted mean disorder (Meseguer et al. 2002) difference=5.0. 95 CILI-8.8; P=O.OI) (Pittler & Ernst. 2003); one trial report of equivalence to and opipramole (Boerner et al. 2003); one trial report of improvement of sleep in patients with anxiety disorder (Lehrl. 2004)

Chamomile Birds to benzodiazepine receptors (Viola No study available Contains coumarins: increase of bleeding Anticoagulants. i effect of sedatives. CYP3A4 et al. 1995) time inhibitor (see Table 3)

Hops Possibly oestrogenic mechanism (Medical Comparable efficacy of a hops-valerian None reported i Effect of sedatives n Economics. 2000) preparation to in the o treatment of sleep disturbance (Schmitz & J: ." Jackel. 1998); no studies on hops alone m... available J: m Z ... Bachflower 38 herbs with postulated differential Not effective (Ernst. 2002) Unclear Unclear » ,. remedies effects. 5 herbs in rescue remedies -< J: m Melatonin Regulation of the body's circadian rhythm. Possibly effective in delayed sleep phase Daytime sleepiness (Herxheimer & Petrie. Anticoagulants. i effect of sedatives C n endocrine secretions and sleep pattern; i (N-acetyl-5- disorder. no clear-cut effect in primary 2003); i depressive mood (Carman et al. (Herxheimer & Petrie. 2003) z m methoxy- GABA binding (Munoz-Hoyos et al. 1998) insomnia (MacMahon et al. 2005); inconclusive 1976) III ) evidence for effectiveness as insomnia treat- Z ment in Alzheimer's disease (Cardinali et al. ."III 2002; Singer et al. 2003); may improve initial -< n sleep quality in older adults with insomnia :I: j; (Olde Rikkert & Rigaud. 2001) ... ,. w -< GABA, gamma-aminobutyric acid; CYP3A4. cytochrome P3A4; HRSA. Hamilton Rating Scale for Anxiety; NMCD. Natural Medicines Comprehensive Database. ~ m ". :D Z m '" m m -I » Table 3 Antidepressants and augmentation: St John's wort ..

Postulated mechanism Effectiveness' Side-effects Potential drug interactions of action

MAOI inhibition and GABAergic activity Six meta-analyses v. placebo using HRSD scores with Similar to SSRls, photosensitivity Serotonergic antidepressants; CYP3A4, IA2 and (Cott, 1997), monoamine reuptake (Perovic trend toward reduced effect size Linde etal, 1996: (Whiskey etal, 2001) 2C9 induction: HIV protease inhibitors, HIV non- & Muller, 1995; Neary & Bu, 1999), OR=2.67 (1.78-4.01); Williams et ai, 2000: RR=1.9 nucleoside reverse transcriptase inhibitors, upregulation of 5HT'A and 5HT 2Areceptors (1.2-2.8); Whiskey etal, 200 I: RR=1.98 (1.49-2.62); warfarin, cyclosporin, oral contraceptives, anti- (Teufel-Mayer & Gleitz, 1997); modulation Werneke et ai, 2004b: RR=I.73 (1.40-2.14); Roder et ai, 2004: convulsants, digoxin and (Committee of cytokine production (Thiele et ai, 1994) RR= 1.5I (1.28-1.75)2; Linde et ai, 2005: major depression - on Safety of Medicines & Medicines Control RR=2.06 (1.65-2.59) (smaller trials), 1.15(1.02-1.29) (larger Agency, 2000) trials), not restricted to major depression - RR=6.13 (3.63- 10.38) (smaller trials), 1.71 (1.40-2.09) (larger trials), Linde et ai, 2005: all studies,' RR=1.71 (1.40-2.09) Four meta-analyses v. standard antidepressants Linde et ai, 1996: OR=I.IO (0.93-1.31) compared with TCAs or ; Whiskey et ai, 200 I: RR= 1.00 (0.93-1.09) compared with TCAs, maprotiline or SSRls; Roder et ai, 2004: RR=0.96 (0.85-1.08) compared with TCAs, maprotiline or SSRls and RR=0.85 (0.75-0.97) in mild or moderate depression; Linde et ai, 2005: RR=I.OI (0.93-1.10) for all trials, RR= 1.03 (0.93-1.14) compared with TCAs or maprotiline, RR=0.98 (0.85-1.12) compared with SSRls

RCT, Szegedi et ai, 2005: RR=1.I8 (0.98-1.42) compared with paroxetine4

I. 95% Cl in parentheses. 2. Calculated by changing the baseline to enable comparison with the other meta-analyses: original RR=0.66 (0.57-0.88). 3. Calculated from all studies (random effect size) and not included in original paper; subgroup analysis reports fixed effect size. 4. Calculated from the reported figures of treatment responses, not included in original paper. MAOI, monoamine oxidase inhibitors; GABA, gamma-aminobutyric acid: 5HT, 5-hydroxytryptamine; HRSD, Hamilton Rating Scale for Depression: OR, odds ratio: RR, risk ratio; TCAs, tricyclic antidepressants; SSRls, selective serotonin reuptake inhibitors: RCT, randomised controlled trial; CYP3A4, cytochrome P3A4. Table 4 Antidepressants and augmentation: supplements

Substance Postulated mechanism of action Effectiveness Side-effects Potential drug interactions

Selenium Antioxidant; brain had a preferential No study available Acute toxicity: nausea causes vomiting, nail Potential! effect of affinity for selenium (Benton, 2002). changes, irritability and weight loss; chronic simvastatin/ Selenium facilitates the conversion ofT4 toxicity: resembles arsenic combination used with a selenium/beta-caro- intoTI (Sher, 2001) toxicity (Werneke, 2003) tene/vitamins C and E supplement (Brown et aI, 2001). Other statins may also be affected (NMCD,2004c) Folicacid Cofactor in neurotransmitter synthesis: Two pooled studies using HRSD and Caution in pernicious anaemia: not to be ! Effect of , , pheno- methylation homocysteine to methionine, addition of folic acid to antidepressants given without vitamin B,,; large doses can and pyrimethamine (NMCD, 2004(1) the immediate precursor of S-adenosyl- RR=0.47 (0.24-0.92); effect possibly lead to agitation, insomnia, confusion and methionine (Bottigleri et 01, 2000; Morris dose-dependent; folic acid alone not increased seizure frequency et 01, 2003) effective (Taylor et 01,2004) S-adenosyl- As above Parenteral S-adenosylmethionine Induction of mania in patients with bipolar Serotonergic antidepressants methionine superior to placebo (Bressa, 1994); affective disorder (Friedel et aI, 1989; comparable efficacy to in Mischoulon & Fava, 2002); significantly better two RCTs (Delle Chiaie et 01, 2002; tolerated than TCAs (Delle Chiaie et 01,2002; Pancheri et 01, 2002); oral S-adenosyl- Mischoulon & Fava, 2002; Pancheri etal, 2002); methionine requires high dose more rapid onset of effect (Fava et aI, 1995) (1600 mg; Delle Chiaie et aI, 2002) Omega-3 fatty Influences catecholaminergic, serotonergic Results of two small trials with short r INR with high or changing doses r Effect of warfarin, aspirin and non-steroidal acids and cholinergic neurotransmission, end-points inconclusive (Marangell (Fugh-Bergman, 2000) anti-inflammatory drugs (Fugh-Bergman, n o modulation of signal transmission et 01,2003; Su et 01,2003); successful 2000); serotonergic antidepressants? :I ... mechanisms in neuronal membranes, augmentation of antidepressant mr- :I modulation of prostaglandins and ion treatment reported (Nemets et aI, m Z channels (Haag, 2003) 2002); r of remission period when added -I J> :D to lithium in bipolar affective disorder -< :I (Stoll et aI, 1999) m tI T4, thyroxine; n, thyronine; HRSD, Hamilton Rating Scale for Depression; RR, risk ratio; RCTs, randomised controlled trials; TCA, tricyclic antidepressants; INR, international normalised ratio; NMCD, Natural Medicines Comprehensive n Database. Z m III z ... III -< n :I: ;; -I :D III -< '" 0. m ;JIJ Z '"m m m -I ...)0

Table 5 Antipsychotics, augmentation and treatment of tardive dyskinesia

Substance Postulated mechanism of aaion Effeaiveness Side-effeas Potential drug interaaions

Rauwolfia ! Dopamine availability: blocks vesicular More effective than placebo in patients with Depression, seizures, extrapyramidal r Effea of antipsychotics and , (includes storage of monoamines, which can then be chronic schizophrenia with regard to general reaaions, blood pressure changes and severe bradycardia with digitalis glycosides, reserpine) degraded by monoamine oxidases (Spinella, mental state and behavioural disturbance heart rate (NMCD, 2004e) ! effect of levodopa, hypertension in 2001) (Malamud et aI, 1957); adjunaive treatment to combination with sympathomimetics antipsychotics (Wolkowitz, 1993) (Medical Economics, 2000) Omega-3 fatty SeeTable4 Meta-analysis of five small studies inconclu- SeeTable4 See Table 4 acids sive; the use of omega-3 fatty acids remains experimental until larger trials are conducted (Joy et aI, 2003) Melatonin Antioxidant, also attenuates dopaminergic Two small RCTs led to inconclusive results; SeeTable2 SeeTable2 aaivity in the striatum and dopamine duration of tardive dyskinesia and melatonin release from the hypothalamus (lohr et aI, dosage may influence treatment outcome 2003; Shamir et aI, 2001) (Shamir et aI, 2000, 2001) Vitamin E Antioxidant Meta-analysis of ten small trials of uncertain SeeTable I SeeTable I quality indicate that vitamin E proteas against deterioration of tardive dyskinesia but there is no evidence that vitamin E improves symp- toms (Soares & McGrath, 2001). One recent trial reports significant improvement of ab- normal involuntary movements (Zhang et aI, 2004)

RCTs, randomised controlled trials; NMCD, Natural Medicines Comprehensive Database. Table 6 Anti-addictives

Substance Postulated mechanism of action Effectiveness Side effects Potential drug interactions

Ibogaine and its derivative Blocks sensitised dopamine response One small open trial only: tested in Cholinesterase inhibitor: can lead to Cholinergic and anticholinergic drugs 18-MC for nicotine, cocaine to chronic and cocaine seven with opiate misuse: three cholinergic toxicity (NMCD, 20040; (NMCD, 20040 and opiate addiction administration (Maisonneuve & Glick, remained abstinent at 14 weeks bradycardia (Maisonneuve & Glick, 2003); may alter morphine induced (Sheppard, 1994); otherwise evidence limited 2003); ibogaine but not 18-MC: dopamine release in nucleus accumbens to case studies (Spinella, 200 I) significant cerebellar toxicity (Maisonneuve & Glick, 2003); binds to the 18-MC only tested in animal experiments; (Maisonneuve & Glick, 2003) cocaine site of the serotonin transporter ! morphine, cocaine and intake in rats

(Staley et ai, 1996); 18-MC binds to the (Rezvani et ai, 1997; Glick et ai, 2000) NMDA receptor (Mash etal, 1995) Valerian for benzodiazepine See Table 2 May improve sleep in patients withdrawing SeeTable2 SeeTable2 addiction from (Poyares et ai, 2002); no controlled trials available

Passion flower for , Cannabis: unclear, benzoflavones may Opiates: effective as adjuvant therapy See Table 2 SeeTable2 benzodiazepine, nicotine and decrease tolerance and withdrawal to demonstrated in one small opiate addiction symptoms (Dhawan et ai, 2002a); opiates: RCT (Akhondzadeh et ai, 200 Ib) use of anxiolytic effect, see Table 2 St John's wort for alcohol Not fully understood, and possibly related ! Alcohol cravingdemonstrated in SeeTable3 SeeTable3 addiction to reducing serotonin, dopamine, animal experiments only (De Vry et ai, 1999; n noradrenaline and GABA reuptake Rezvani et ai, 1999; Overstreet et ai, o 3: 2003a,b); effect may be dose-dependent "V (Rezvanietal,1999,2003) .. Kudzu for alcohol m Ingredient , counteracts the Only one small trial in humans available None reported (NMCD, 2004g) Theoretically with anticoagulants, 3: m addiction anxiogenic effects associated with alcohol showing no difference to placebo (Shebek & aspirin, cardiovascular agents and Z »~ withdrawal; may also have -like Rindone, 2000) hypoglycaemic drugs (NMCD, '" -< properties (Overstreet et ai, 2003b) 2004g) :I m C 18-MC, 18-methoxycoronaridine; NMDA, N-methyl-D-aspartate; GABA, gamma-aminobutyric acid; RCT, randomised controlled trial; NMCD, Natural Medicines Comprehensive Database. n z m III Z "V III -< n J: » ~ - '" ~ -< WERNEKE ET AL

cocaine and opiate users (Maisonneuve & RCTs are required to assess other those from a wide variety of cultural Glick, 2003). Ibogaine also binds to the promising agents such as selenium and backgrounds. This may lead to higher cocaine site of the serotonin transporter S-adenosylmethionine for the treatment acceptance and adherence compared with (Staley et ai, 1996), but its therapeutic of depression, ideally in individuals conventional drugs, making it important value is limited as it is highly neurotoxic showing the corresponding deficiencies to be 'willing and prepared to work in part- and can cause irreversible cerebellar at baseline. This may lead to new thera- nership with patients' beliefs and prefer- damage (Maisonneuve & Glick, 2003); as peutic approaches for treatment-resistant ences - provided their actions are safe' a result, further clinical stUdies have been depression. Valerian and passion flower (Brugha et ai, 2004). Also, we do not know abandoned. A synthetic derivative 18- should be tested as anxiolytics and seda- whether the agreed use of complementary methoxycoronaridine has similar reported tives; their potential value in the treat- medicines could in itself improve insight effects but no cerebellar toxicity or specific ment of addiction also requires further and subsequently lead to greater adherence effects on the serotonin transporter clarification. The role of omega-3 fatty to conventional treatment regimens. This (Maisonneuve & Glick, 2003). To date acids as an adjunct to antipsychotics emphasises the importance of further re- 18-methoxycoronaridine has only been and melatonin as a treatment or prophy- search on complementarymedicinesfocusing tested in animal experiments where it has lactic agent for tardive dyskinesia remain on promising agents such as passion flower, been shown to reduce cocaine, morphine ambiguous, both requiring trials with valerian and S-adenosylmethionine, which and alcohol intake in rats (Rezvani et ai, sound methodology. appear to be obvious candidates for further 1997; Glick et ai, 2000). We have outlined only a limited range RCTs. In addition, it might be important to Passion flower has also been used to of complementary medicines used for the consider patients' attitUdes and preferences ameliorate the effects of opiate, cannabis, treatment of common psychiatric problems. in future studies, possibly targeting those benzodiazepine and nicotine addiction, Clearly there are many more remedies that demanding complementary medicines. but clinical data are limited (Dhawan et may be taken to improve general health or Finally, clinicians need to be aware of ai, 2002a,b, 2003; Akhondzadeh et ai, to counter the side-effects of conventional side-effects associated with complementary 2001b). Likewise, valerian has been tried treatments. Clinicians need to be aware of medicines and any interactions with other in benzodiazepine withdrawal (Poyares et and enquire about such forms of self- treatments. They should be able to identify ai, 2002)and StJohn's wort has beenused medication, since all remedies may interact hazards, advising patients accordingly and for the treatment of alcohol dependence with prescribed medication or have avoiding uncritical encouragement of po- (De Vry et ai, 1999; Rezvani et ai, 1999; associated side-effects in their own tentially harmful use. Ignorance in this Overstreet et ai, 2003b), but effectiveness right. For instance, patients may take area, given the independent usage of com- has not been established. Kudzu, Japanese phyto-oestrogens, such as black colosh plementary medicines, may lead to criticism arrowroot (Puerarialobata), has tradition- (Actaea racemosa), wild yam (Dioscorea and possibly litigation (Cohen & Eisenberg, ally been used for the treatment of alcoholic composita) or dong quai (Angelicasinensis) 2002). Equally, patients should be encour- hangover. The active ingredient, purerarin, to counter sexual side-effects, and this aged to disclose information about counteracts the anxiogenic effects asso- might pose a problem in patients with complementary medicines to healthcare ciated with alcohol withdrawal (Overstreet oestrogen receptor-positive breast cancer professionals. These discussions need to be et ai, 2003a). Kudzu also contains two po- (Werneke et ai, 2004a). For the same conducted sensitively in order to avoid alie- tent, reversible inhibitors of human alcohol reason, patients may also try evening prim- nating patients who may feel that they have dehydrogenase isozymes (Keung, 1993), rose oil (Oenothera biennis), which could not been taken seriously or have been criti- but an effect has only been demonstrated decrease the effect of sodium cised for using complementary medicines. in vitro (Lin & Li, 1998). One small trial (Miller, 1989). Kelp (Laminaria digitata Such discussions can be complex and may among those with chronic alcohol misuse or Fucus vesiculosus) may be taken to demand more time than is available in has not shown any difference from placebo counter weight gain, but can contain sub- routine clinics. Service models need to be (Shebek& Rindone,2000). Further trials stantial amounts of iodine and can interfere designed to meet this challenge, with con- are required to test its genuine therapeutic with treatment for thyroid function sideration being given to specialist clinics potential, perhaps using more standardised disorders. Iodine taken together with providing regular updated advice to both formulations of the active ingredient. lithium may have additive hypothyroid clinicians and patients. effects (Natural Medicines Comprehensive ACKNOWLEDGEMENT DISCUSSION Database,2004b). Given the complex pattern of potential We thank Mr Oded Horn for his assistancewith Our review demonstrates that the evidence interactions, clinicians should not be afraid interpretation of the meta-analyses. base for the use of psychotropic comple- to discuss complementary medicines with mentary medicines is extremely limited. their patients. Although some patients REFERENCES The best evidence is available for St may choose to use complementary medi- John's wort and kava kava, both of cines as alternatives to conventional treat- Ahlemeyer, B. & Krieglstein, J. (2003) ment, many may decide to use them in Neuroprotectiveeffectsof Ginkgobilobaextract. which are used extensively in various CellularandMolecularLifeSciences,60, 1779-1792. cultures. However, trials of St John's addition to prescribed medications. Com- wort need improved definition of inclu- plementary medicines have - rightly or Akhondzadeh, S., Naghavi, H. R., Vazirian, M., et 01 sion criteria (Werneke et ai, 2004b), wrongly - a very positive 'natural' reputa- (20010) Passionflowerin the treatment of generalized and kava kava has been withdrawn due anxiety: a pilot double-blind randomized controlled trial tion among significant sections of the popu- with oxazepam. journal of Clinical Pharmacy and to concerns about hepatotoxicity. Further lation, and therefore can be popular with Therapeutics, 26, 363-367.

118 COMPLEMENTARY MEDICINES IN PSYCHIATRY

Akhondndeh, S., Kashani, L., Mobaseri, M., et 01 Cott, J. M. (1997) In vitro receptor binding and Fugh.Bennan, A. (2000) Herb-drug interactions. (200Ib) Passionflower in the treatment of opiates inhibition by hypericum perforatum extract. Lancet.355, 134-138. withdrawal: a double-blind randomized controlled trial. Pharmacopsychiatry. 30 (suppl.).108-112. Glick, S. D., Maisonneuve, I. M. & Dickinson, H. A. journalof Clinical Pharmacy and Therapeutics. 26, 369-373. De Vry, J., Maurel, S., Schreiber, R., et 01 (1999) (2000) 18-MC reduces methamphetamine and nicotine Aldennan, C. P. & Kiepfer, B. (2003) Complementary Comparison of hypericum extracts with imipramine and self-administration in rats. Neuroreport, 11,2013-2015. medicine use by psychiatry patients of an Australian in animal models of depression and alcoholism. Haag, M. (2003) Essential fatty acids and the brain. hospital. Annals of Pharmacotherapy. 37, 1779-1784. European Neuropsychopharmacology. 9.61-68. Canadianjournal of Psychiatry.48. 195-203. Amenta, F., Cavallotti, C., Franch, F., et 01 (1989) Delle Chiaie, R., Pancheri, P. & Scapicchio, P. (2002) Muscarinic cholinergic receptors in the hippocampus of Efficacy and tolerability of oral and intramuscular 5- Hamilton, M. (1967) Development of a rating scale for the aged rat: effects of long-term hydergine adenosyl-L-methionine 1.4-butanedisulfonate (SAMe) in primary depressive illness. British journal of Social and administration. Archives Intemationales de the treatment of major depression: comparison with Clinical Psychology.6, 278-296. Pharmacodynamie et de Therapie, 297, 225-234. imipramine in 2 multicenter studies. Americanjournalof Hawkes, WoC. & Hornbostel, L. (1996) Effects of Benjamin, J., Muir, T., Briggs, K., et 01 (2001) A case ClinicalNutrition.76 (suppl.).11725-11765. dietary selenium on mood in healthy men living in a of cerebral haemorrhage - can Ginkgo biloba be Dhawan, K., Kumar, S. & Sharma, A. (20020) metabolicresearch unit.BiologicalPsychiatry.39, 121-128. Reversal of (delta9-THC) by the implicated? Postgraduate Medical journal. 77. 112-113. Herxheimer, A. & Petrie, K. J. (2003) Melatonin for benzoflavone moiety from extract of Benton, D. (2002) Selenium intake. mood and other the prevention and treatment of jet lag.CochraneLibrary. Passifloraincarnata Linnaeusin mice: a possibletherapy aspects of psychological functioning. Nutrition and issue 4. Oxford: Update Software. Neurasciences. 5. 363-374. for addiction.journalof Pharmacyand Pharmacology.54.875-881. Houghton, P.J. (1999) The scientificbasisfor the Benton, D. & Cook, R. (1991) Selenium Dhawan, K., Kumar, S. & Sharma, A. (2002b) reputed activity of Valerian.journalof Pharmacyand supplementation improves mood in a double-blind Nicotine reversal effects ofthe benzoflavone moiety Pharmacology.51.505-512. crossover trial. Biological Psychiatry. 29. 1092-1098. from Passifloraincarnata Linneausin mice.Addiction Itil, T. M., Ahmed, I., Kunitz, A., et 01(1998) The Birks, J., Grimley Evans J. & Van Dongen, M. (2002) Biology.7,435-441. pharmacologicaleffects ofginkgobiloba, a extract. Gingko biloba for cognitive impairment and dementia. Dhawan, K., Dhawan, S. & Chhabra, S. (2003) on the brain of dementia patients in comparison with Cochrane Library. Issue 2. Oxford: Update Software. Attenuation of benzodiazepine dependence in mice by a tacrine. PsychopharmacologyBulletin.34,391-397. Boerner, R. J., Sommer, H., Berger, Wo, et 01 (2003) tri-substituted benzoflavone moiety of Passiflora Jaroszewski, J. Wo,Olafsdottir, E. S., Wellendorph, P., Kava-Kava extract LlI50 is as effective as and incarnata Linneaus:a non-habit forming anxiolytic. et al (2002) Cyanohydrin glycosides of Passiflora: buspirone in generalised anxiety disorder an 8-week - journalofPharmacyandPharmacologicalScience.6, distribution pattern, a saturated cyclopentane derivative randomized. double-blind multi-centre clinical trial in 215-222. from P. guatemalensis. and formation of 129 out-patients. Phytomedicine. 10 (suppl.), 38-49. Diaper, A. & Hindmarch, I. (2004) A double-blind. pseudocyanogenic alpha-hydroxyamides as isolation Bottiglieri, T., Laundy, M., Crellin, R., et 01 (2000) placebo-controlled investigation of the effects of two artifacts. Phytochemistry. 59. 501-511. Homocysteine, folate. methylation. and monoamine doses of a valerian preparation on the sleep. cognitive Joy, C. B., Mumby-Croft, R. & Joy, L. A. (2003) metabolism in depression. journal of Neuralogy. and psychomotor function of sleep-disturbed older Polyunsaturated fatty acid supplementation for Neurosurgery and Psychiatry. 69. 228-232. adults. Phytotherapy Research.18,831-836. schizophrenia. Cochrane Library. issue4. Oxford: Update Bowden, C. L. (2001) Novel treatments for bipolar Dinh, L. D., Simmen, U., Bueter, K. B., et 01 (2001) Software. disorder.Expert Opinionin InvestigatingDrugs. 10.661-671. Interaction of various Piper methysticum cultivars with Jussofie, A., Schmiz, A. & Hiemke, C. (1994) Bressa, G. M. (1994) S-adenosyl-I-methionine (SAMe) CNS receptors in vitro. Planta Medica. 67. 306-311. Kavapyroneenriched extract from Piper methysticum as antidepressant: meta-analysis of clinical studies. Acto Dorn, M. (2000) Efficacy and tolerability of Baldrian as modulator ofthe GABAbindingsite in different Neurologica Scandinavica.154 (suppl.).7-14. versus oxazepam in non-organic and non-psychiatric regions of rat brain. Psychopharmacology.116,469-474. Brown, B. G., Zhao, X. Q., Chait, A., et 01 (2001) insomniacs: a randomised. double blind, clinical Kanowski, S. & Hoerr, R. (2003) Ginkgo biloba Simvastatin and niacin, antioxidant vitamins, or the comparative study. ForschendeKomplementarmedizin und extract EGb761 indementia: intent-to-treat analysesof combination for the prevention of coronary disease. KlassischeNaturheilkunde. 7. 79-84. a 24-week, multi-center. double-blind, placebo- New England journal of Medicine. 29. 1583-1592. Dravid, A. R. (1983) Deficits in cholinergic controlled,randomizedtrial.Pharmacopsychiatry.36, Brugha, T., Rampes, H. & Jenkins, R. (2004) Surely and muscarinic receptors in the hippocampus and 297-303. you take complementary and alternative medicines? striatum of senescent rats: effect of chronic hydergine Psychiatric Bulletin. 28. 36-39. treatment. Archives Internationales Pharmacodynamie et Kessler, R. C., Soukup, J., Davis, R. B., et al (2001) The use of complementary and alternative therapies to Cardinali, D. P., Gvozdenovich, E., Kaplan, M. R., et 01 de Therapie. 264. 195-202. treat anxiety and depression in the United States. (2002) A double blind-placebo controlled study on Eisenberg, D. M., Kessler, R. C., Foster, C., et 01 American journal of Psychiatry. 158. 289-294. melatonin efficacy to reduce anxiolytic benzodiazepine (1993) Unconventional medicine in the United States. use inthe elderly.Neuroendocrinology Letters, 23. 55-60. Prevalence, costs and pattern of use. New England Keung, WoM. (1993) Biochemical studies of a new class of alcohol dehydrogenase inhibitors from Radix puerariae. Carman, J. S., Post, R. M., Buswell, R., et 01 (1976) journal of Medicine. 328. 246-252. Alcoholism.Clinicaland ExperimentalResearch.17,1254-1260. Negative effects of melatonin on depression. American Ernst, E. (2002) "Flower remedies": a systematic review journal of Psychiatry. 133. 1181-1186. ofthe clinicalevidence.Wiener Klinische Wochenschrift, Klepser, T. B. & Klepser, M. E. (1999)Unsafe and Chatterjee, S. S., Nolder, M., Koch, E., et 01 (1998) 30.963-966. potentiallysafe herbal therapies. American journal of Antidepressant activity of hypericum perforatum and Ernst, E. & Cassileth, B. R. (1999) How useful are Health-System Pharmacy.56, 125-138. hyperforin: the neglected possibility. Pharmacopsychiatry. unconventional cancer treatments? European journal of Knaudt, P. R., Cannor, K. M., Weisler, R. H., et al 31 (suppl.),7-15. Cancer. 35. 1608-1613. (2001) Alternative therapy use by psychiatric outpatients. Chevallier, A. (1996) The Encyclopedia of Medicinal Fava, M., Giannelli, A., Rapisarda, V., et 01(1995) journal of Nervousand Mental Disease.187.692-695. Plants. London: Dorling Kindersley. Rapidityofonset ofthe antidepressant effect of Krasawski, M. D., McGehee, D. S. & Moss, J. (1997) Coffin, A. I. (1845) BotanicGuide to Health and Natural parenteralS-adenosyl-L-methionine.Psychiatry Natural inhibitors of cholinesterases: implications for Research.56. 295-297. Pathologyof Diseases.London:J.Caudwell. adverse drug reactions. Canadian journal of Anaesthesia, 44. 525-534. Cohen, M. H. & Eisenberg, D. M. (2002) Potential Fisher, A. A., Purcell, P. & Le Couteur, D.G. (2000) physician malpractice liability associated with Toxicityof Passifloraincarnata L.journalof Clinical Lee, B. M., Lee, S. K. & Kim, H. S. (1998) Inhibition of Toxicology.38,63-66. complementary and integrative medicinal therapies. oxidative DNA damage, 8-0HdG, and carbonyl Annals of Internal Medicine. 136. 596-603. Food Standards Agency. Expert Group on Vitamins contents in smokers treated with antioxidants (vitamin Committee on Safety of Medicines & Medicines and Minerals (2003) SateUpperLevelsfor Vitaminsand E. vitamin C, beta-carotene and red ginseng).Cancer Letters. 132. 219-227. Control Agency (2000) Reminder: St John's wort Minerals.http://www.foodstandards.gov.uk (Hypericum perforatum) interactions. CurrentProblemsin Friedel, H. A., Goa, K. L. & Benfield, P. (1989) Lehrl, S. (2004) Clinical efficacy of kava extract WS Pharmacovigilance.26. 6-7. S-adenosyl-L-methionine.A review of its 1490 in sleep disturbances associated with anxiety Corrigan, J. J. Jr (1982) The effect of vitamin E on pharmacologicalproperties and therapeutic potential in disorders. Results of a multicenter. randomized. warfarin-induced vitamin K deficiency. Annals of the liver dysfunction and affective disorders in relation to its placebo-controlled, double-blind clinical trial. journal of New YorkAcademy of Sciences.393. 361-368. physiologicalrole incellmetabolism. Drugs.38.389-416. Affective Disorders. 78. 101-110.

119 WERNEKE ET AL

Le PoncinoLafitte, M., Rapin, J. R., Duterte, D., et 01 Miller, L. G. (1989) Herbal medicinals: selected clinical Pancheri, P., Scapicchio, P. & Chiaie, R. D. (2002) A (1985) Learning and cholinergic neurotransmission in old considerations focusing on known or potential drug- double-blind, randomized parallel-group, efficacy and animals: the effect of Hydergine. Pharmacology. 16 herb interactions. Archives of Internal Medicine, 158, safety study of intramuscular S-adenosyl-L-methionine (suppl.). 57-63. 2200-2211. 1.4-butanedisulphonate (SAMe) versus imipramine in patients with major depressive disorder. International Lewis, R., Wake, G., Court, G., et 01 (1999) Non- Mischoulon, D. & Fava, M. (2002) Role of S-adenosyl- journal of Neuropsychopharmacology.5, 287-294. ginsenoside nicotinic activity in ginseng species. L-methionine in the treatment of depression: a review of Phytotherapy Research, 13, 59-64. the evidence. American journal of Clinical Nutrition, 76 Perovic, S. & Miiller, W. E. (1995) Pharmacological (suppl.), 11585-11615. profile of hypericin extract. Effect on serotonin reuptake Liede, K. E., Haukka, J. K., Saxen, L. M., et 01 (1998) by postsynaptic receptors. Arzneimittelforschung, 45, Increased tendency towards gingival bleeding caused by Morris, M., Fava, M. & Jaques, P. F. (2003) Depression 1145-1148. joint effect of alpha-tocopherol supplementation and and folate status inthe US population. Psychotherapie acetylsalicylic acid. Annals of Medicine, 30. 542-546. Psychosomatik, 72, 80-87. Pittler, M. H. & Ernst, E. (2003) Kavaextract for treating anxiety.CochraneLibrary.issue4. Oxford: Un, R. C. & U, T. K. (1998) Effects of isoflavones on Miiller, W. E., Singer, A., Wonnemann, M., et 01(1998) Update Software. alcohol pharmacokinetics and alcohol-drinking behavior Hyperforin represents the neurotransmitter reuptake in rats. American journal of Clinical Nutrition. 68 (supplJ, inhibiting constituent of hypericum extract. Poyares, D. R., Guilleminault, C., Ohayon, M. M., et 15125-15155. Pharmacopsychiatry. 31 (suppl.),16-21. 01 (2002) Can valerian improve the sleep of insomniacs after benzodiazepine withdrawal? Progressin Linde, K., Ramirez, G., Mulrow, C. D., et 01(1996) St Muno%-Hoyos, A., Sanche%oForte, M., Molina- Neuropsychopharmacology and Biological Psychiatry. 26, John's wort for depression an overview and meta- - Carballo, A., et 01(1998) Melatonin'srole as an 539-545. analysis ofthe randomised clinicaltrials. BMj, 313, 253-258. and neuronal protector: experimental Rezvani, A. H.,Overstreet, D. H., Yang,Y., et 01 Linde, K., Berner, M., Egger, M., et 01 (2005) St john's and clinicalevidence.journalof ChildNeurology.13, (1997) Attenuation of alcohol consumption by a novel wort for depression. Meta-analysis of randomised 501-509. nontoxic ibogaineanalogue (18-methoxycoronaridine) in controlled trials. British journal of Psychiatry. 186,99-107. Naturai Medicines Comprehensive Database (20040) alcohol-preferringrats.Pharmacology.Biochemistryand Lohr, J. B., Kuc%enski, R. & Niculescu, A. B. (2003) http: ffwww.naturaldatabase.com. Product search; Kava. Behavior.58,615-619. Oxidative mechanisms and tardive dyskinesia. CNS Natural Medicines Comprehensive Database Rezvani, A. H., Overstreet, D. H., Yang, Y., et 01 Drugs. 17,47-62. (2004&)http://www.naturaldatabase.com. Product (1999) Attenuation of alcohol intake by extract of Mac/ennan, K. M., Darlington, C. L. & Smith, P. F. search: Iodine. Hypericum perforatum (St. John's Wort) in two different (2002) The CNS effects of Ginkgo biloba extracts and strains of alcohol-preferring rats. Alcohol and Alcoholism, Natural Medicines Comprehensive Database ginkgolideB.Progressin Neurobiology.67.235-257. 34,699-705. (2004c) http://www.naturaldatabase.com. Product MacMahon, K. M. A., Broomfield, N. M. & Espie, search: Selenium. Rezvani, A. H.,Overstreet, D. H., Perfumi, M., et of C. A. (2005) A systematic review of the effectiveness of (2003) Plant derivatives in the treatment of alcohol Natural Med:cines Comprehensive Database oral melatonin for adults (18 to 65 years) with delayed dependency. Pharmacology.Biochemistry and Behavior,75, sleep phase syndrome and adults (18 to 65 years) with (2004d) http: ffwww.naturaldatabase.com. Product 593-606. search: Folicacid. primary insomnia.Current Psychology Reviews,1,103-113. Roberts, C. G. & Ladenson, P.W. (2004) Natural Medicines Comprehensive Database Maisonneuve, I. M. & Glick, S. D. (2003) Anti- Hypothyroidism. Lancet. 363, 793-803. addictive actions of an iboga alkaloid congener: a novel (20040) http;ffwww.naturaldatabase.com. Product search: Indiansnakeroot. Roder, C., Schaefer, M. & Leucht, S. (2004) Meta- mechanism for a novel treatment. Pharmacology. analysis of effectiveness and tolerability oftreatment of Biochemistry and Behavior. 75, 607-618. Naturai Medicines Comprehensive Database (20040 mild to moderate depression with St. John's Wort. Malamud, W., Barton, W.E., Flemlng, A. M., et oJ http: ffwww.naturaldatabase.com. Product search:Iboga. Fortschritte der Neurologie Psychiatrie, 72, 330-343. (1957) The evaluation ofthe effects of derivatives of Naturai Medicines Comprehensive Database (2004g) Rauwolfia inthe treatment of schizophrenia. American Sano, M., Ernesto, C., Thomas, R. G., et 01 (1997) A http://www.naturaldatabase.com.Productsearch:Kudzu. journal of Psychiatry.114,193-200. controlled trial of selegeline. alpha-tocopherol or both as treatment for Alzheimer's disease. New England journal Neary, J. T. & Bu, Y. (1999) Hyperforin inhibits uptake Marangell, L. B., Martlne%, J. M., Zboyan, H. A., et of Medicine, 336, 1216-1222. of serotonin and norepinephrine in astrocytes. Brain 01(2003) A double-blind, placebo-controlled study of Research,816, 358-363. Schelosky, L., Raffauf, C. & Jendroska, K. (1995) Kava the omega-3 fatty acid docosahexaenoic acid inthe and dopamine antagonism. journal of Neurology. treatment of major depression. Americanjournalof Nemets, B., Stahl, Z. & Belmaker, R. H. (2002) Neurosurgery and Psychiatry. 58, 639-640. Psychiatry.160,996-998. Addition of omega-3 fatty acid to maintenance Schmit%, M. & Jackel, M. (1998) Comparative study Markstein, R. (1985) Hydergine: interaction with the medication treatment for recurrent unipolar depressive disorder. American journal of Psychiatry. 159,477-479. for assessing quality of life of patients with exogenous neurotransmitter systems in the central nervous system. sleep disorders (temporary sleep onset and sleep journal of Pharmacology.16 (suppl.), 1-17. Oken, B. S., Stor%bach, D. M. & Kaye, J. A. (1998) interruption disorders) treated with a hops-valerian The efficacy of ginkgo biloba on cognitive function in Mash, D. C., Staley, J. K., Pablo, J. P., et 01 (1995) preparation and a benzodiazepine drug. Wiener Alzheimer disease. Archivesof Neurology. 55. 1409-1415. Properties of ibogaine and its principal metabolite (12- Medizinische Wochenschri/t, 148.291-298. hydroxyibogamine) at the MK-801 binding site of the Olde Rikkert, M. G. & Rigaud, A. S. (2001) Melatonin Schreiter-Gasser, U. & Gasser, T. (2001) A NMDAreceptor complex. NeuroscienceLetters, 192, in elderly patients with insomnia. A systematic review. 53-56. comparison of cholinesterase inhibitors and ginkgo Gerontology and Geriatrics, 34,491-497. extract in treatment of Alzheimer dementia. Fortschritte Mathews, J. M., Etheridge, A. S. & Black, S.R. Olin, J., Schneider, L., Novit, A., et 01(2001) der Medizin Originalien, 119,135-136. (2002) Inhibition of human cytochrome P450 activities Hyderginefor dementia.CochraneLibrary.issue4. Shamir, E., Barak, Y., Plopsky, I., et 01 (2000) Is by kavaextract and . Drug Metabolism and Oxford; Update Software. Disposition, 3D, 1153-1157. melatonin treatment effective for tardive dyskinesia? Ondri%ek, R. R., Chan, P. J., Patton, W. C., et of (1999) journal of Clinical Psychiatry. 61.556-558. Matthews, M. K. Jr (1998) Association of Ginkgo biloba Inhibitionof humansperm motility by specific herbs Shamir, E., Barak, Y. & Shaiman, I. (2001) Melatonin with intracerebralhemorrhage. Neurology.50, 1933-1934. used in . journal of Assisted treatment for tardive dyskinesia: double-blind. placebo- Matthews, s. C., Camacho, A., Lawson, K., et 01 Reproduction and Genetics, 16,87-91. controlled, crossover study. Archives of General (2003) Use of herbal medications among 200 Overstreet, D. H., Keung,W.M., Rezvani, A. H., et at Psychiatry. 58, 1049-1052. psychiatric outpatients: prevalence, patterns of use, and (20030) Herbal remedies for alcoholism:promises and Shebek, J. & Rindone, J. P. (2000) A pilot study potential dangers. General Hospital Psychiatry. 25, 24-26. possiblepitfalls.Alcoholism,ClinicalandExperimental exploring the effect of kudzu root on the drinking habits Medical Economics (2000) PDR(Physicians'Desk Research,27,177-185. of patients with chronic alcoholism. journal of Alternative Reference)for Herbal Medicines (2nd edn). Montvale,NJ: and Complementary Medicine, 6, 45-48. Overstreet, D. H., Kraiic, J. E., Morrow, A. L., et 01 Medical Economics Company. (2003&)NPI-03IG (puerarin) reduces anxiogenic effects Sheppard, S. G. (1994) A preliminary investigation of Meseguer, E., Taboada, R., Sanche%, V., et 01 (2002) of alcohol withdrawal or benzodiazepine inverse or 5- ibogaine: case reports and recommendations for Life-threatening parkinsonism induced by kava-kava. HT() . Pharmacology.Biochemistry and further study. journal of SubstanceAbuse and Treatment, Movement Disorders, 17,195-196. Behavior.75, 619-625. 11,379-385.

120 COMPLEMENTARY MEDICINES IN PSYCHIATRY

Sher, L. (2001) Role ofthyroid hormones inthe effects of selenium on mood, behavior, and cognitivefunction. Medical Hypotheses,57,480-483. CLINICAL IMPLICATIONS

Singer, C., Tractenberg, R. E., Kaye, J., et of (2003) Alzheimer's Disease Cooperative Study. A multicenter, . Depending on the inclusion criteria chosen, between 8 and 57% of psychiatric placebo-controlled trial of melatonin for sleep patients (most commonly those with depression and anxiety) use complementary disturbance in Alzheimer's disease, Sleep, 26, 893-901. medicines. Soares, K. V. S. & McGrath, J. J. (2001) Vitamin E for neuroleptic-induced tardive dyskinesia. Cochrone Library. . Cliniciansmust be prepared to discussthe use of complementary medicinewith issue 4. Oxford: Update Software. patients who prefer a holistic approach to treatment. Spinella, M. (2001) Psychotherapeutic herbs. InThe Psychophormacology of , p.278. . Cliniciansneed to be aware of side-effects associated with complementary Cambridge, MA: MIT Press. medicines and their interactions with conventionaltreatments. Staley, J. K., Ouyang, Q. & Pablo, J. (1996) Pharmacological screen for activities of 12- LIMITATIONS hydroxyibogamine: a primary metabolite of the indole alkaloid ibogaine. Psychopharmacology. 127, 10-18. . The evidencebase for the use of psychotropic complementary medicines is Stevinson, C. & Ernst, E. (2000) Valerian for insomnia: a systematic review of randomized clinical trials. Sleep extremely limited and randomised controlled trials of promising agents are urgently Medicine, 1,91-99. needed. Stoll, A. L., Severus, W. E., Freeman, M. P., et 0' (1999) Omega 3 fatty acids in bipolar disorder: a . Often, the active ingredient in herbal formulations has not been identified, which preliminary double-blind, placebo-controlled trial. leads to problems with standardisation of extracts and dose recommendations. Archives of Generol Psychiatry. 56,407-412,

Su, K. P., Huang, S. Y., Chlu, C. C., et 0' (2003) . Discussionsof complementary medicine use maydemand more time than is Omega-3 fatty acids in major depressive disorder. A availablein routine clinics. preliminary double-blind, placebo-controlled trial. European Neuropsychopharmacology.13,267-271.

Szegedi, A., Kohnen, R., Dienel, A., et 0' (2005) Acute treatment of moderate to severe depression with hypericum extract WS5S70 (St John's wort): URSULAWERNEKE,MRCPsych,Division of Health Service Research,Institute of Psychiatry,and Division of randomised controlled double blind non-inferiority trial Psychiatry.Homerton University Hospital,TREVORTURNER, FRCPsych,Division of Psychiatry,Homerton against paroxetine. BMj, 330, 503-506. University Hospital,STEFANPRIEBE,FRCPsych,Unit for Socialand Community Psychiatry.Barts and The Tabet, N., Birks, J. & Grimley Evans J. (2000) Vitamin London, NHS Trust,Queen Mary Schoolof Medicineand Dentistry. London,UK E for Alzheimer's disease. Cochrone Librory. issue 4. Oxford: Update Software. Correspondence: Or Ursula Werneke, Division of Psychiatry, Homerton University Hospital, East Wing, Tang, F., Nag,S., Shiu, S. Y., et 0' (2002) The effects of Homerton Row, London E9 6SR,UK. E-mail: [email protected] melatonin and Ginkgo biloba extract on memory loss and choline acetyltransferase activities in the brain of (First received2 April 2004, final revision 17March 2005, accepted3 May 2005) rats infused intracerebroventricularly with beta- amyloid. Life Sciences, 71, 2625-2631. Vogeler, B. K., Pittler, M. H. & Ernst, E. (1999) The depression. International Clinical Psychopharmacology.16, Taylor, M. J., Carney, 5., Geddes, J., et 0' (2004) Folate efficacy of ginseng. A systematic review of randomized 239-252. for depressive disorders. Cochrane Librory. issue I. controlled trials. European journal of Clinical Oxford: Update Software. Pharmacology.55, 567-575. Williams, J.W., Mulrow, C. D. & Chiquette, E. (2000) A systematic review of newer pharmacotherapies for Teufel-Mayer, R. & Gleltz, J. (1997) Effect of long term Wang, J. L., Patten, S. B. & Russell, M. L. (2001) depression inadults. Annalsof InternalMedicine,132, administration of hypericin extracts on the affinity and Alternative medicine use by individuals with major 743-756. density of the central serotonergic 5HTIA and 5HT 2A depression. Canadianjournal of Psychiatry.46, 528-533. receptors. Pharmacopsychiatry. 30 (suppl. 2), 113-116. Wolfman, C., Viola, H., Paladini, A., et 0' (1994) Watanabe, H., Kakihana, M., Ohtsuka, 5., et 0' Possible anxiolytic effects of chrysin, a central Thiele, B., Brink, I. & Ploch, M. (1994) Modulation of (1997) Randomized, double-blind,placebo-controlled benzodiazepine receptor isolated from Passiflora cytokine expression by hypericin extract. journal of studyof supplementalvitaminEon attenuationofthe coerulea. Pharmacology.Biochemistryand Behavior,47,1-4, Geriatric Psychiatry and Neurology.7 (suppl. I),560-562. developmentof nitratetolerance.Circulation,96, 2545-2550. Wolkowltz, O. M. (1993) Rational polypharmacy in Tian, J. Z., Zhu, A. H. & Zhong, J. (2003) A follow-up schizophrenia. Annals of Clinical Psychiatry. 5, 79-90, study on a randomized, single-blind control of King's Werneke, U. (2003) Alternative nutrition therapies in Brain pills in treatment of memory disorder in elderly cancer - the evidence. Clinical Nutrition Update, 8, 6-8. Zhang, X. Y., Zhou, D. F., Cao, L. Y., et 0' (2004) The people with MC! in a Beijing community. Zhongguo effect of vitamin E treatment on tardive dyskinesia and Werneke, U., Earl, J., Seydel, C., et 0' (20040) Potential Zhong YaoZo Zhi, 28,987-991. blood superoxide dismutase: a double-blind placebo- health risks of complementary alternativemedicines in controlled trial. Clinical Psychopharmacology.24, 83-86. Unutzer, J., Klap, R., Sturm, R., et 0' (2000) Mental cancer patients.BritishjournalofConcer,90,408-413. disorders and the use of alternative medicine: results Ziegler, G., Ploch, M. & Miettinen-Baumann, A. Werneke, U., Horn, O. & Taylor, D. (2004b) How from a national survey. Americanjournalof Psychiatry. (2002) Efficacy and tolerability of valerian extract LI 156 157,1851-1857. effective isSt John'swort? The evidence revisited.journal compared with oxazepam in the treatment of non- of Clinical Psychiatry.65, 611-617. van Dongen, M., van Rossum, E., Kessels, A., et Q' organic insomnia - a randomized, double-blind, (2003)Ginkgoforelderlypeoplewithdementiaand Wettstein, A. (2000) Cholinesterase inhibitors and comparative clinicalstudy. European journal of Medical age-associated memory impairment: a randomized gingkoextracts - are they comparable inthe treatment Research,25, 480-486. clinicaltrial. ClinicalEpidemiology.56, 367-376. of dementia? Comparison of publishedplacebo- Zimmerman, R. A. & Thomspon, I. M. Jr (2002) controlled efficacy studies of at least six months. Viola, H., Wasowski, C. & Levi de Stein, M. (1995) Prevalence of complementary medicine in urologic Phytomedicine,6, 393-401. Apigenin, a component of Matricaria recutita flowers, is practice. A review of recent studies with emphasis on a central benzodiazepine receptors-ligand with Whiskey, E.,Werneke, U. & Taylor, D. (2001) A use among prostate cancer patients. Urology Clinicsof anxiolyticeffects. PlantaMedica,61,213-216. systematic review of hypericum perforatum in North America, 29, 1-9.

121