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Home , Ginkgolide, Kava

APPLIED EVIDENCE New research findings that are changing clinical practice

Monica Vermani, for mental illness: Hon.BSc, MA Stress, Trauma, Anxiety, Effectiveness and interaction Rehabilitation Treatment (S.T.A.R.T.) Clinic for Mood & Anxiety Disorders, Toronto, with conventional medicines Canada; Adler School of Professional Psychology, Some herbs do work as claimed; all have the potential Chicago, Ill

for downside activity as well Irena Milosevic, Hon.BSc University of Toronto, Toronto, Practice recommendations ■ Ginkgo has shown promise in improv- Canada ■ Many of your patients may be self- ing cognitive function in dementia, and Fraser Smith, BA, ND treating with herbal preparations. Ask its side effects are few and uncommon Canadian College of candidly about this possibility, and (A, for cognitive function in dementia). Naturopathic Medicine, become familiar with the increasing Monitor carefully if there is concomi- Toronto, Canada evidence on efficacy and safety of tant anticoagulant therapy. Martin A. Katzman, BSc, alternative treatments MD, FRCPC ased on epidemiologic estimates, Stress, Trauma, Anxiety, ■ A large meta-analysis and a Cochrane it may be that 20% to 30% of Rehabilitation Treatment Review both suggest St. John’s Wort (S.T.A.R.T.) Clinic for Mood & your patient population is using (A) is as effective as conventional anti- B Anxiety Disorders, Toronto, alternative/complementary medicines.1 and more effective than Canada; Department of Twenty percent of adults who take Psychiatry, Faculty of for mild to moderate depres- prescription medicine also rely on Medicine, University of sion. With patients taking St. John’s Toronto herbal products,2 and patients who use Wort and a conventional antidepres- herbal products the most are those with sant, remain alert for a potentiating chronic conditions.3 effect, “serotonin syndrome.” Use with Included in this group are persons caution if the patient must also receive with mental health problems, who, anticoagulants, oral contraceptives, or compared with the general population, antiviral agents. report a much greater use of alternative ■ The efficacy and safety of (B, treatments, including herbal and home- in terms of psychological well-being) opathic remedies.4 These remedies, and evening primrose (C) for depres- when used to treat psychiatric symp- sion are not well established. toms, may produce changes in mood, ■ Kava-kava (A, for short-term treatment thinking, or behavior, and they may for anxiety treatment) has well-known interact with a number of conventional .3 CORRESPONDING AUTHOR properties, but its potential Martin A. Katzman, BSc, MD, Largely uncharted territory. adverse effects, particularly liver toxici- With the FRCPC, Stress, Trauma, ty, dramatically reduce its usefulness. exception of St. John’s Wort for depres- Anxiety, Rehabilitation Treatment (S.T.A.R.T.) Clinic , though commonly used for sion and ginkgo for dementia, minimal evidence is currently available to recom- for Mood & Anxiety Disorders, anxiety (C, for and anxiety), 790 Bay Street, Toronto, is not well supported by good data. mend the use of herbal medicines as the Ontario, Canada M5G 1N8. primary treatment for mental illness. E-mail: [email protected]

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TABLE 1 Safety of common herbal products

HERB INTERACTIONS WITH ADVERSE EFFECTS

St. John’s Wort Anticoagulants, oral Photodermatitis, delayed hyper- contraceptives, antiviral sensitivity, gastrointestinal tract agents, digoxin, SSRIs upset, dizziness, dry mouth, Potential for other interactions , restlessness, constipation due to induction of hepatic Mania and hypomania

Evening primrose Phenothiazines, nonsteroidal Nausea, softening of the stool, anti-inflammatory drugs, headache corticosteroids, beta-blockers, Worsening of epilepsy symptoms anticoagulants

Ephedra agents, MAO inhibitors, Hypertension, palpitations, antihypertensives, tachycardia, stroke, seizures, death Psychosis, affective disturbances

Ginseng MAO inhibitors, , Insomnia, hypertension, diarrhea, , warfarin restlessness, anxiety, Mania

Kava-kava , , Dizziness, mild gastrointestinal disturbance, yellow discoloration of skin, hair, and nails Hepatitis Kava dermopathy

FAST TRACK Valerian Barbiturates, , Headaches, excitability, uneasiness, St. John’s Wort CNS depressants gastrointestinal effects, dizziness, cardiac disturbances was superior Ginkgo Anticoagulants Headaches, gastrointestinal tract to placebo upset, nausea, vomiting, skin allergy and comparable Yohimbine Sibutramine, heart/blood pressure Headaches, sweating, agitation, with conventional medications, lithium, , hypertension, restlessness antidepressants alcohol Psychotic symptoms, mania, seizures

Although some herbs have been found investigators pursue intensive clinical to be effective at specific doses for spe- research to establish safety (TABLE 1) and cific conditions, there is no evidence to efficacy. Additionally, greater under- show their superiority to conventional standing of the biochemical and phar- treatments, nor has their safety macological effects of these herbs may been established for use during pregnan- uncover novel treatments or yield fresh cy and lactation.8 insights into basic disease mechanisms.9 Helping patients navigate. Neverthe- The herbal remedies discussed in less, our patients are increasingly turn- this article are those commonly used for ing to alternative therapies, and it is psychiatric conditions. Their effective- therefore critical that we clinicians avail ness and potential for adverse side ourselves of current knowledge and that effects and interactions are assessed.

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■ Depression St. John’s wort Deficiencies to overcome St. John’s Wort (Hypericum perforatum L) ecause many alternative options do not require the is a popular herbal treatment readily used Bapproval of the US Food and Drug Administration by the public in various forms, such as (FDA), products sold in health food stores can be purchased tablets and teas. Efficacy of hypericum— without a prescription or the provision of any clinical advice one of the hypothesized active ingredients or professional review. The quality of many herbal prepara- in St. John’s Wort—in the treatment of tions is thus unpredictable, with the content varying not depression was reported in the texts of the only from brand to brand but also from batch to batch.5 physicians Hippocrates, A working knowledge of the pharmacologic data Pliny, and Galen, and it continued to and clinical literature is necessary to properly counsel, be cited throughout the Classical, diagnose, and treat patients who may be using herbal Renaissance, and Victorian eras. Its con- products. However, 1 study reported that only 5% of temporary usage as an has British doctors claimed more than a poor knowledge of been supported by more rigorous evidence ,6 and another survey revealed that most than any other herbal remedy.9 psychiatrists who do not recommend herbal products Efficacy. Evidence of efficacy in mild to avoid doing so because they feel uncomfortable with their moderate depression has been reported in current knowledge of alternative therapies.7 Alarmingly, a meta-analysis of 23 randomized trials the latter study reported that among psychiatrists who do with a total of 1757 outpatients, in which not recommend herbal treatments, the safety of such treat- extracts of St. John’s Wort alone (20 of 23 ments is not an issue in their decision-making process. trials) or in combination with other herbs (3 of 23) were tested against placebo (15 trials) or antidepressant drugs (8 trials).10 Wort as an antidepressant. St. John’s Wort was reported to be clearly Mechanisms of action. The mecha- superior to placebo and comparable with nisms for the antidepressant effects of St. conventional drug treatment, with lower John’s Wort are not fully understood, side-effect and dropout rates. Similarly, a although monoamine oxidase (MAO) recent Cochrane Review of 27 trials and inhibition, inhibition of serotonin FAST TRACK 2291 patients concluded that St. John’s expression, serotonin inhibition, Learn which herbs Wort was more effective than placebo in and reduction of cytokine expression have treating mild to moderately severe depres- all been suggested as means of its activity.9 can inhibit or sion; however, there was inadequate evi- -drug interactions. Evidence sug- induce the dence to determine whether the herb was gests St. John’s Wort contains both cytochrome P-450 as effective as traditional antidepressants.11 inhibitory and inducing constituents for The superiority of hypericum to place- the cytochrome P-450 (CYP) system, system bo has been called into question, however, resulting in both inhibition and induction by a large-scale, multicenter, double-blind on the CYP system.14 Consequently, it’s dif- case report tabulation. The study, conduct- ficult to predict which drugs St. John’s ed with 200 patients across 11 academic Wort will interact with in a significant medical centers in the United States, found way.15 Best estimates of its activity suggest no evidence that St. John’s Wort was more it has minimal short-term activity; when efficacious than placebo.12 Another such used for a longer period, it will inhibit the trial also concluded that St. John’s Wort CytP450-3A4, 2C19, and 2D6 systems was not an effective treatment for major (TABLE 2). Therefore, St. John’s Wort may depression. In addition, the herb was alter the blood levels of such medications found to be no different than , as anticoagulants,16 oral contraceptives,18 which was also indistinguishable from the and antiviral agents,19 possibly resulting in placebo, further confusing the issue.13 serious consequences.16,17 Exercise caution Strength of recommendation (SOR) is level when initiating treatment for patients A for the evidence in support of St. John’s already taking St. John’s Wort.

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TABLE 2 Effects of common herbs on cytochrome P-450 enzymes

CYTOCHROME P-450 CYTP450-3A4 CYTP450-2C19 CYP450-2D6

St. John’s Wort ++++ inhibition (short-term?) +++ inhibition ++ inhibition

Long-term induction in intestinal wall99

Kava-kava100 ++ inhibition ++ inhibition ++ inhibition

Valerian + inhibition + inhibition 0

Fish oil, omega-3 +++ inhibition ++++ inhibition + inhibition fatty acids

Key: ++++ = very potent; ++ = potent (detectable); + = mildly potent; 0 = does not inhibit Note: Caution should be undertaken when developing tables such as these, as the data came from a variety of in vivo and in vitro animal and human studies using simplified models (eg, cDNA-expressed CYP enzymes) of which there are significant interspecies variations in the activity of these systems. As well, in the presence of some pathological inflammatory states such as during an infection, the activity of the CYP can be modulated through cytokines and other mediators of inflammation.101

The potential of St. John’s Wort to There are several anecdotal reports of interact with standard prescribed antide- mania or hypomania associated with the pressants, possibly to produce a “serotonin herb. For example, O’Breasail and syndrome,” is also a concern. Gordon20 Argouarch24 reported 2 cases of persons reported a case in which a woman taking with no history of bipolar disorder who St. John’s Wort became groggy, weak, and developed hypomanic episodes after taking FAST TRACK lethargic shortly after taking a single 20- St. John’s Wort. Likewise, Moses and Reports of mg dose of . This patient had Mallinger25 reported 3 cases of possible tolerated St. John’s Wort and paroxetine mania induction associated with the herb. ginseng’s separately, suggesting a drug-herb interac- effectiveness tion.3 St. John’s Wort has also been impli- Ginseng for depression cated in reducing blood levels of digoxin This herb is derived from the of when the two are taken together,21 and 1 Panax ginseng and has been used as a cure- conflict study documented that 8% of psychiatrists all in Eastern folk medicine for thousands dramatically treating patients who had used St. John’s of years.26 Today, both Chinese ginseng (P Wort reported drug interactions between ginseng CA Meyer) and North American the herb and another agent.22 ginseng (P quinquefolius L) are associated Adverse effects. In general, fewer with the treatment of mood and anxiety adverse effects are seen with hypericum disorders and are used to reduce stress and than with conventional antidepressants fatigue and to improve endurance. but they may include photodermatitis, Efficacy. A of 16 delayed hypersensitivity, gastrointestinal double-blind randomized controlled trials tract upset, dizziness, dry mouth, seda- found that ginseng did not improve cogni- tion, restlessness, and constipation. Use tive function or psychomotor and physical of St. John’s Wort is contraindicated dur- performance.27 Another review reported ing pregnancy and lactation, for patients conflicting results from several studies.28 who experience intense exposure to For example, 1 double-blind randomized strong sunlight, and for patients with a controlled trial of postmenopausal women pheochromocytoma.23 who received either a placebo or ginseng

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for 16 weeks revealed the superiority of ginseng on measures of psychological Methods used for this review well-being.29 Another double-blind ran- iterature searches were conducted using Medline, domized controlled trial, however, failed LPsycInfo, and the Cochrane Library electronic databases, to find an effect of ginseng on positive and by consulting bibliographies of pertinent publications. affect, negative affect, or total mood We focused primarily on meta-analyses and large-scale case disturbance in 83 healthy adults who took report tabulations at an evidence level of 1b. Additionally, the herb for 8 weeks.30 Thus, at best, articles selected included those that discussed the use of SOR=B for the evidence in support of herbal treatments for mental illness, as well as those that ginseng, but only at best in relation to addressed drug-herb interactions between herbal and psychological well-being. traditional psychiatric drug treatments. Mechanisms of action. The key active components of Panax ginseng are gin- senosides, a group of steroidal saponins the herb. Thus, at best, SOR=C for the evi- that target a multitude of tissues to dence in support of evening primrose. produce pharmacologic responses. The Mechanisms of action. Gamma lino- overall of ginseng is lenic acid, a precursor of prostaglandin E complex due to the ability of ginsenosides and several other active substances, is the to initiate multiple actions in the same main constituent responsible for the ther- tissue. Attele and colleagues31 provide an apeutic effects of evening primrose.37 in-depth review of these mechanisms. Herb-drug interactions. This herb has Herb-drug interactions. Ginseng may the potential to interact with phenoth- potentiate the effect of MAO inhibitors,32 iazines, nonsteroidal anti-inflammatory stimulants (including ), and drugs, corticosteroids, beta-blockers, and haloperidol.33 In addition, a case study anticoagulants.9 suggests a probable interaction with Adverse effects. Although it is gener- warfarin.34 ally safe, evening primrose oil has occa- Adverse effects. Reported side effects sionally exacerbated the symptoms of include insomnia, hypertension, diarrhea, epilepsy.39 Other adverse effects are nau- FAST TRACK restlessness, anxiety, and euphoria.35 There sea, softening of the stool, and headache.37 Support for is at least 1 report of ginseng-induced mania, which occurred within 4 to 10 evening primrose days of a patient’s interrupting a lithium Ephedra (Ephedra sinica) is an evergreen is primarily and treatment.26 shrub native to Asia used in traditional anecdotal Chinese medicine for thousands of years. Evening primrose In recent decades, ma-huang, the extract Evening primrose (Oenothera biennis L) is derived from this herb, has been a com- a native to North America. The oil mon ingredient in many natural supple- pressed from its seed is marketed as a ments that promote increased energy, nutritional supplement, and it has been mood enhancement, and weight loss.40,41 In used to treat many disorders, including early 2004, the FDA banned the sale of premenstrual syndrome (PMS) and dietary products containing ephedra due premenstrual dysphoric disorder to concerns over its adverse effects.42 (PMDD), both which are marked by affec- Efficacy. Research on ephedra’s effica- tive disturbances.36,37 cy is largely focused on its role in weight Efficacy. A systematic review38 of the loss, and there is little evidence that evalu- efficacy of evening primrose oil in the ates it as a mood enhancer. A comprehen- treatment of PMS revealed few clinical tri- sive meta-analysis43 assessed 20 controlled als of adequate methodology. The authors trials with a treatment duration of at least found only 2 well-controlled studies, both 8 weeks and concluded that ephedra, which failed to show beneficial effects for when administered alone or with caffeine,

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promotes modest short-term weight loss and it has euphoric and (0.9 kg/month more than placebo). properties, although its effect on arousal However, not all of the included studies and alertness appears to be minimal.9 It is were randomized or double-blind, and no commonly used in Europe and North data were available on long-term effects. A America for its anxiolytic effects. smaller systematic review44 of 5 double- Efficacy. A Cochrane review54 of 6 dou- blind studies also found the combination ble-blind randomized controlled trials that of ephedra and caffeine stimulated weight used a common outcome measure loss, but it was unclear whether 2 of the (Hamilton Anxiety Scale) concluded that trials were randomized. Thus, SOR=A for kava is significantly superior to placebo as the evidence in support of weight loss in a short-term treatment for anxiety. The the short term. There is no evidence in sup- authors note, however, that further investi- port of it as a mood-enhancing treatment. gation is required to determine long-term Mechanisms of action. The primary efficacy and safety. Another meta-analy- constituents of ephedra are ephedrine-type sis55 of 7 double-blind randomized con- . As a sympathomimetic trolled trials also suggests that, relative to a at both α- and β-adrenergic receptors, placebo, kava is an efficacious treatment ephedrine enhances cardiac rate and con- for anxiety. Thus, SOR=A for the evidence tractibility, peripheral vasoconstriction, in support of short-term efficacy in kava in bronchodilation, and central nervous sys- anxiety. However, long-term data in terms tem stimulation.41 of safety and efficacy has not been shown. Herb-drug interactions. Ephedra Mechanisms of action. Kavapyrones should not be used with anesthetic are the major constituents of this herb and agents,45 MAO inhibitors,46,47 antihyperten- are responsible for its pharmacologic activ- sives, or antidepressants.41 ity. The mechanisms of their anxiolytic Adverse effects. The relative risk of effect are still unclear. One line of research adverse reactions to ephedra is more than suggests that kavapyrones might mediate 100 times greater than that of all other effects by influencing gamma- FAST TRACK herbs.40 As noted by Jacobs and Hirsch,48 aminobutyric acid (GABA)(A) receptor The risk between 1993 and 1997 the FDA had binding,56–58 whereas another theory posits received 34 notices of death and reports of that kavapyrones are a reversible inhibitor of serious approximately 800 medical and psychi- of human platelet MAO-B.52 Others have side effects atric complications all directly linked to suggested the inhibition of voltage-gated with kava ephedra. A more recent review49 indicated ion channels as a potential mechanism of that hypertension, palpitations, tachycar- action.59,60 far outweighs dia, stroke, seizures, and death are related Herb-drug interactions. This herb has its mild to ephedra use. The herb has also been the potential to interact with benzo- anxiolytic effect noted to induce symptoms of psychosis diazepines,61 and the combination with and affective disturbances.50,51 central nervous system depressants like and barbiturates can produce synergistic effects.56,62 ■ Anxiety Adverse effects. Liver damage has Kava-kava been reported in patients who use kava.63–65 Kava-kava is derived from the dried rhi- A recent study66 analyzed 29 cases of pur- zome of the oceanic kava plant ( ported liver dysfunction in addition to 7 methysticum), and it has been cultivated cases that have already been published; the for thousands of years throughout the authors concluded that kava ingestion was South Pacific, where it is consumed as a the direct cause of liver injury in 3 cases, a psychotropic drink for recreational and probable cause in 21 cases, and a possible medicinal purposes.52 Kava has been cause in 12 cases. The most frequent liver shown to alleviate anxiety symptoms,53 injury was necrosis. Other adverse effects

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of this herb include dizziness, mild gas- a anxiolytic, and further research is neces- trointestinal disturbance, and a temporary sary to assess the effect of valerian in yellow discoloration of skin, hair, and insomnia and anxiety nails.67 In addition, long-term administra- Mechanisms of action. Valerian’s con- tion of kava at higher doses my cause stituents include of the scaling of the skin on the extremities, also volatile oil (including valeric acid), iridoids known as kava dermopathy.68 (valepotriates), alkaloids, furanofuran lig- nans, and free amino acids such as GABA, Valerian tyrosine, arginine, and .72 The Valerian (Valerian officinalis) is a root precise mechanisms of action are still extract, with purported healing properties unclear, though it has been suggested that that can be traced to ancient Greece and all of the active constituents act synergisti- Rome. Today, valerian root preparations cally to produce a clinical response. are used for their sedative, anxiolytic, and Research has also demonstrated modula- antidepressant properties. The herb, a tion of GABA neurotransmission and GABA agonist,9 is commonly used in the receptor function (see Houghton73 for a treatment of sleeplessness and the manage- comprehensive review of valerian’s phar- ment of anxiety associated with muscle macology). tension.10 Herb-drug interactions. Valerian has Efficacy. A recent systematic review of the potential to prolong thio-, pental-, and randomized clinical trials (including -induced sleep and should, reports in all languages) assessed the effica- therefore, not be combined with barbitu- cy of valerian in patients with insomnia.69 rates.74,75 It may also potentiate the sedative Nine randomized, double-blind, placebo- effects of anesthetics and other central controlled trials satisfied the inclusion nervous system depressants.45 criteria; however, even in these studies Adverse effects. Adverse affects with questionable methods in randomization, this product are rare, but when they occur blinding, compliance, withdrawal, con- they may include headaches, excitability, founding variables, diagnostic criteria, and uneasiness, gastrointestinal effects, dizzi- FAST TRACK statistical analysis rendered contradictory ness, and cardiac disturbances.76–78 Data confirming results, and the authors concluded that evidence for valerian in the treatment of valerian’s effects insomnia is inconclusive. ■ Dementia as a somnolent Data to confirm valerian’s effective- Ginkgo and anxiolytic ness as an anxiolytic are also minimal. One Ginkgo extracts are derived from one of randomized placebo-controlled pilot study the oldest known tree species (Ginkgo are minimal examined the effects of valerian on gener- biloba L). They have been used in tradi- alized ; 36 patients were tional Chinese medicine for 5000 years for treated with placebo, , or valer- a variety of purposes and are believed to be ian extract for 4 weeks.70 The authors helpful in the treatment of memory impair- found a significant reduction in the psychic ment caused by dementia.79 The herb is factors of anxiety with diazepam and also used to treat stress, fatigue, chronic valerian. However, the study was limited cerebrovascular insufficiency, and cerebral by the small number of patients in each trauma, and to improve endurance.9 group, relatively low dosages of the active Efficacy. Evidence for ginkgo’s efficacy agents, and a short duration of treatment. is encouraging, but more rigorous research Similar studies71 suffer from the same is needed. Kleijnen and Knipschild80 shortcomings, and thus further research is reviewed 40 controlled trials on the use of necessary to assess the effect of valerian on ginkgo to treat “chronic cerebral insuffi- anxiety. Thus, SOR=C for the evidence in ciency.” Only 8 of the studies were deemed support of valerian as a somnolent and as to be of good quality, although all but

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TABLE 3 function who had not previously respond- Recommendations for clinicians ed to papaverine showed improvement with a daily dose of 60 mg of ginkgo over 12 to 18 months.9 However, further Ask your patients if they are using natural health products or seeing a natural health practitioner. Recognize that they may be covertly research must be undertaken in this self-medicating with herbal or alternative treatments. Better-studied domain, in part because this trial was not alternative treatments should be substituted. blinded, with both doctors and patients aware of who was receiving the ginkgo Create an environment where patients are not reluctant to disclose the use of natural health care. treatment. Thus, SOR=A for the evidence in sup- If the patient is seeing a naturopathic doctor, obtain contact port of ginkgo as a cognitive enhancer in information so that the specifics of the therapy can be requested. mild to moderate dementia, and B for the Communicate directly with the naturopathic clinician about changes evidence in support of ginkgo as a treat- in treatment choices that are taking place in the ongoing care of the ment for erectile dysfunction. patient. This may often include sending consultation letters and other Mechanisms of action. Ginkgo leaves information to all individuals involved in the treatment of the patient. contain several bioactive compounds, Acquire good reference materials on natural health products. including , (ginkgo- Suggestions: Natural Alternatives to Prozac by Michael T. Murray, lide, bilbobide), and organic acids. ND, and The Textbook of Natural Medicine by Joseph Pizzorno, ND Although the mechanisms of action are and Michael T. Murray, ND. only partially understood, the main effects Never underestimate the potential risk of possible chemical appear to be related to its antioxidant inter-actions between medications. properties, which require the synergistic action of the principal constituents.82 These Make contact with a community naturopathic doctor who can compounds act as free radical scavengers.83 answer questions about specific natural health products. Other pharmacologic actions involve anti- hypoxic and antiplatelet effects.84 1 found clinically significant improvement Herb-drug interactions. Researchers in symptoms including memory loss, con- have suggested that ginkgo may potentiate FAST TRACK centration difficulties, fatigue, anxiety, and other anticoagulants or increase bleeding Ginkgo depressed mood. over time,85,86 which can be attributed to Another meta-analysis79 identified B, a potent inhibitor of platelet- was superior more than 50 articles on the effect of gink- activating factor needed for inducing to placebo go on the cognitive function in Alzheimer arachidonate-independent platelet aggre- in delaying patients, but only 4 studies were found to gation.87 Caution should be exercised be properly blinded and placebo- when ginkgo is taken in conjunction with the course controlled with well-characterized sub- anticoagulant treatment (including ) of dementia jects. The authors concluded that gingko or when there is a risk of bleeding (eg, appears to have a modest effect on cogni- peptic ulcer disease and subdural tive function in Alzheimer’s but note that hematoma).9,86 further research is necessary. Adverse effects. Side effects from gink- A systematic review by Ernst and col- go appear to be relatively uncommon; leagues81 concluded that ginkgo was supe- however, they may include headaches, gas- rior to a placebo in delaying the clinical trointestinal tract upset, nausea, vomiting, course of dementia. The authors reported and a skin allergy to the ginkgo fruit.17,88 on 9 placebo controlled, double-blind randomized trials including 1497 patients in their analysis. ■ Sexual dysfunction Ginkgo has also been used to treat Yohimbine impotence, including antidepressant- Yohimbine is an derived from the induced sexual dysfunction. In 1 trial, 60 cortex of the Central African tree patients with proven arterial erectile dys- Corianthe yohimbe.89 The bark of the tree

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TABLE 4 Internet resources about herbal products0

The Natural Pharmacist ($) www.tnp.com Evidence-based content developed and reviewed byphysicians and pharmacologists; sections on herbs and supplements, health conditions, and drug interactions; information referenced

Natural Medicines Comprehensive Database ($) www.naturaldatabase.com Well-referenced, comprehensive database

Complementary and Alternative Therapies (Bandolier) www.jr2.ox.ac.uk/bandolier/ booth/booths/altmed.html Evidence-based content; abstracts of systematic reviews, meta-analyses, or other studies about herbal therapies

National Center for Complementary and Alternative Medicine www.nlm.nih.gov/nccam/camonpubmed.html Access to PubMed’s CAM database

HerbMed www.herbmed.org Access to scientific evidence about the use of herbs for health

$ = paid subscription required; all websites accessed April 5, 2005. Table adapted from Gardener.102

was used traditionally to enhance virility. alpha2-adrenergic antagonist. Its blocking Today, yohimbine is still reputed as an activity increases the release of noradrena- aphrodisiac and used as a remedy for erec- line and the firing rate of noradrenergic tile problems.90 neurons in the central nervous system.92 Efficacy. Overall, the efficacy of Herb-drug interactions. Yohimbine yohimbine in the treatment of erectile dys- should not be taken with sibutramine, a function appears promising, although, as serotonin and reuptake FAST TRACK with studies of other herbal products, clin- inhibitor. The concomitant use of the 2 Yohimbine ical trials often suffer from methodological products could unmask the peripheral effect flaws. Carey and Johnson91 conducted 4 of sibutramine and produce negative cardio- is superior independent meta-analyses to examine the vascular effects.93 Potential interactions also to placebo as effects of yohimbine alone or in combina- exist with heart or blood pressure medica- a treatment tion with other drugs in controlled and tions,94 lithium,95 morphine,96 and alcohol.97 uncontrolled trials. The authors found Adverse effects. Adverse effects are not for erectile positive results for yohimbine across all 4 common with yohimbine; however, they dysfunction analyses, but they note that the highest- may include headaches, sweating, agita- quality data were derived from controlled tion, hypertension, and restlessness.98 clinical trials when yohimbine was admin- Yohimbine has also been reported to con- istered on its own. In their analysis, this tribute to psychotic symptoms, mania, and included 242 patients across 4 studies. seizures, though such occurrences are not Another systematic review yielded similar well documented.9 results: a meta-analysis of 7 randomized, placebo-controlled trials including 419 patients demonstrated that yohimbine is ■ Growing need superior to placebo as a treatment for erec- for the 2 worlds to merge 89 tile dysfunction. Thus, SOR=A for the One of the most frequent scenarios evidence in support of yohimbine as a encountered by the naturopath is the treatment for erectile dysfunction. patient who is taking a psychotropic Mechanisms of action. Yohimbine is an and wants to explore natural

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solutions to reduce the drug’s unpleasant 8. Wong AHC, Smith M, Boon HS. Botanical medicine in psychiatry. Psychiatry Rounds 1999; 3(2):1–5. side effects or to enhance general well 9. Wong AHC, Smith M, Boon HS. Herbal remedies in being. Sharing information is the key to a psychiatric practice. Arch Gen Psychiatry 1998; healthy treatment regimen for such indi- 55:1033–1044. 10. Linde K, Ramirez G, Mulrow CD, Pauls A, viduals (TABLES 3 AND 4). The patient Weidenhammer W, Melchart D. St. John’s wort for should inform both the physician and depression: An overview and meta-analysis of ran- domized clinical trials. BMJ 1996; 313:253–258. naturopath about health care decisions, 11. Linde K, Mulrow CD. St. John’s wort for depression the naturopath must encourage the patient (Cochrane Review). In: The Cochrane Library, Issue 4, to be candid with the physician about pro- 2003. Chinchester, UK: John Wiley & Sons, Ltd. 12. Shelton RC, Keller MB, Gelenberg A, et al. posed treatments, and the physician can be Effectiveness of St. John’s wort in major depression. helpful by communicating to the natur- JAMA 2001; 285:1978–1986. 13. Davidson JRT. Effect of Hypericum perforatum (St opath the extent of the patient’s disorder. John’s wort) in major depressive disorder. JAMA 2002; Professionally, one must consider before 287:1807–1814. asking a patient to discontinue one agent or 14. Strandell J, Neil A, Carlin G. An approach to the in vitro evaluation of potential for enzyme the other whether the alternative treatment inhibition from herbals and other natural remedies. might be improving the patient’s condition Phytomedicine 2004; 11:98–104. 15. Zhou S, Gao Y, Jiang W, Huang M, Xu A, Paxton JW. or reducing negative side effects caused by Interactions of herbs with cytochrome P450. Drug the psychotropic medication. On one hand, Metab Rev 2003; 35:35–98. withdrawing the drug can destabilize the 16. Ernst E. 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