251 Pages

Integrative Medicine in Primary Care, Part II: Disease States and Body Systems, An Issue of Primary Care Clinics in Office Practice - E-Book


Gain access to the library to view online
Learn more


Complementary and alternative medicine encompasses a wide range of modalities, including acupuncture, herbs and supplements, naturopathy, and body and mind therapies. The use of these healing methods is increasing rapidly, and more and more patients are approaching primary care physicians with questions about them. The purpose of this issue is to help doctors understand the evidence supporting and refuting complementary and alternative medicine techniques so they can provide patients with answers. This is the second of a two-part series, and it focuses on application of complementary and alternative medicine techniques to disease states and body systems.



Published by
Published 17 June 2010
Reads 0
EAN13 9781455700608
Language English
Document size 2 MB

Legal information: rental price per page 0.0293€. This information is given for information only in accordance with current legislation.

Primary Care Clinics in Office Practice, Vol. 37, No. 2, June 2010
I S S N : 0095-4543
d o i : 10.1016/S0095-4543(10)00034-5
C o n t r i b u t o r sPrimary Care Clinics in Office Practice
Integrative Medicine in Primary Care, Part II:
Disease States and Body Systems
Roger Zoorob, MD, MPH, FAAFP
Department of Family and Community Medicine, Meharry Medical College, 1005 Dr DB
Todd Boulevard, Nashville, TN 37208, USA
Vincent Morelli, MD
Department of Family and Community Medicine, Meharry Medical College, 1005 Dr DB
Todd Boulevard, Nashville, TN 37208, USA
Joel J. Heidelbaugh, MD, FAAFP, FACG
ISSN 0095-4543
Volume 37 • Number 2 • June 2010
Forthcoming issues
Complementary and Alternative Medicine Usage for Behavioral Health
Herbals Used for Diabetes, Obesity, and Metabolic Syndrome
Integrative Medicine and Gastrointestinal Disease
Alternative Therapies for Common Dermatologic Disorders, Part 1
Alternative Therapies for Common Dermatologic Disorders, Part 2
Common Respiratory Diseases
Alternative Prevention and Treatment of Cardiovascular Disease Part 1
Alternative Prevention and Treatment of Cardiovascular Disease, Part 2
Women’s Health: Selected TopicsMusculoskeletal Disorders
Integrative Medicine Approach to Chronic Pain
IndexPrimary Care Clinics in Office Practice, Vol. 37, No. 2, June 2010
ISSN: 0095-4543
doi: 10.1016/S0095-4543(10)00036-9
Forthcoming issues+
Primary Care Clinics in Office Practice, Vol. 37, No. 2, June 2010
ISSN: 0095-4543
doi: 10.1016/j.pop.2010.02.013
Common Clinical Applications of Complementary and Alternative
Joel J. Heidelbaugh, MD
Ypsilanti Health Center, 200 Arnet Suite 200, Ypsilanti, MI 48198,
E-mail address: jheidel@umich.edu
Joel J. Heidelbaugh, MD Consulting Editor
As I stated in the March 2010 issue of Primary Care Clinics in O ce Practice dedicated
to complementary and alternative medicine (CAM), compiled and edited by Dr Adam
Rind0eisch, CAM continues to permeate our lives in popularity, prevalence, and
necessity. Moreover, the future of health care will need to warmly embrace provisions
for CAM services across all disciplines. Public curiosity and demand for CAM will only
increase, so as medical providers, our knowledge and integration must stay ahead of the
game to satisfy the needs of patients. On almost a daily basis, it continues to astonish
me how many of my patients initially reject a prescription for a standard drug only to
ask for a suitable herbal or vitamin alternative to treat their acute and chronic
This second installment of Primary Care Clinics in O ce Practice dedicated to CAM
explores alternative therapies related to speci7c organ system–based diseases and
chronic conditions, which is truly a unique collection of reviews. The issue concludes
with an integrative medicine approach to chronic pain and musculoskeletal disorders.
As primary care clinicians treat increasingly greater numbers of patients a: icted with
chronic pain issues (think: How many chronic pain specialists are readily available in
your referral network?), and as we grow more skeptical about engaging in chronic
opioid management, alternative options must be explored and trialed to prove e cacy.The greatest challenge here may be through enlightening patients that
non–narcoticbased options exist and motivating them to engage in self-directed exercise programs,
such as yoga.
Similarly, not only are CAM options for pulmonary, gastrointestinal, and
dermatologic conditions growing in availability but also patients are learning to ask for
them by name. This trend only makes us, as clinicians, look unprepared, unless we have
suitable references readily available during patient encounters. The widespread
acceptance and use of probiotics for the treatment of various gastrointestinal disorders,
including irritable bowel disease, is a prime example of this trend, which has become a
billion dollar industry. Lastly, the relationship between CAM and the prevention of
cardiometabolic syndrome cannot be denied. Guidelines for appropriate nutrition as
well as nutritional supplementation are often numerous and con0icting. Important
questions, including, “What eCect does coenzyme Q10 have on statin therapy?” and
“What can chromium and magnesium supplementation do to improve outcomes in
diabetes mellitus?” have the potential to have an impact on daily clinical care.
I oCer my collective gratitude to Dr Roger Zoorob and Dr Vincent Morelli for
recruiting talented authors to create a natural complement to the March issue on CAM
integration into primary care. I 7nd this volume to be a unique arrangement of
practical reviews that primary care clinicians can rely on in their daily practices to
augment current knowledge in the treatment of commonly encountered diseases in the
ambulatory care setting. Despite a lack of many strict evidence-based guidelines based
solely on randomized controlled clinical trials, this issue provides readers with novel
therapies based on clinical evidence that can be easily integrated into daily practice.Primary Care Clinics in Office Practice, Vol. 37, No. 2, June 2010
ISSN: 0095-4543
doi: 10.1016/j.pop.2010.02.012
Complementary and Alternative Medicine
Roger J. Zoorob, MD, MPH
Department of Family and Community Medicine, Meharry Medical
College, 1005 Dr DB Todd Boulevard Nashville, TN 37208, USA
E-mail address: rzoorob@mmc.edu
E-mail address: morellivincent@yahoo.com
Vincent Morelli, MD
Department of Family and Community Medicine, Meharry Medical
College, 1005 Dr DB Todd Boulevard Nashville, TN 37208, USA
E-mail address: rzoorob@mmc.edu
E-mail address: morellivincent@yahoo.com
Roger J. Zoorob, MD, MPH Guest Editor
Vincent Morelli, MD Guest Editor
Herbal therapy is usually underreported by patients, but the available evidence
suggests that it is used by more than 15% of the US population. The cost of such@
therapy exceeds 6 billion dollars per year. Complementary and alternative medicine
(CAM), which includes herbs, supplements, and modalities such as acupuncture and
chiropractic, is even more extensively used. According to the National Health Statistics
reports, the overall prevalence of use comprises more than 38% of the US population.
The costs are enormous, approaching 35 billion dollars in out-of-pocket expenses each
It is with enthusiasm and hesitation that we accepted the invitation to be the Guest
Editors for this issue. The enthusiasm stems from the enormous use by our patients of
this therapy, which is not subjected to any strict regulation. Consequently, we hope to
shed some light on what is available and what evidence exists for its use by primary
care providers. At the same time, we were hesitant to dive into this topic given the
scarcity of evidence-based literature and randomized clinical trials and the di culty of
interpretation. No matter how deeply one reviews the evidence, it is insu cient. We
alert the reader to this limitation any time this subject is approached.
Primary care providers should query their patients about CAM use in an open and
unassuming manner. They must advise patients about potential side e ects, what works
and what does not, and the possible interaction with allopathic management. However,
always remember that the greatest medical invention of all time—penicillin—was the
product of a mold and that some ovarian cancer cures were derived from plants. Hence,
without nontraditional experimentation, we may never discover great cures. On the
other hand, we must be wary of undocumented and unsubstantiated use that may
dispose patients to adverse effects.
Finally, our thanks to Elsevier for allowing us the opportunity to present this topic to
our readers who are primary care providers and trainees. In spite of the limitations, we
hope this issue can guide them through some of the pathways of this enormous and
stillonly-partially-charted area of care.Primary Care Clinics in Office Practice, Vol. 37, No. 2, June 2010
ISSN: 0095-4543
doi: 10.1016/j.pop.2010.02.002
Complementary and Alternative Medicine Usage for Behavioral
Health Indications
*Michele M. Larzelere, PhD , James S. Campbell, MD, Marta Robertson, MD
Department of Family Medicine, Louisiana State University Health Sciences Center, 200
West Esplanade Avenue, Suite 409, Kenner, LA 70065, USA
* Corresponding author.
E-mail address: mlarze@lsuhsc.edu
Evidence on the use of complementary and alternative medicine (CAM) modalities in the treatment of
depression, anxiety, sleep disorders, and attention-de, cit/hyperactivity disorder (ADHD) is reviewed.
There is strong evidence to support the use of St. John’s wort (SJW) in depression, and growing
support for the use of omega-3 fatty acids and S-adenosyl-l-methionine as potential adjuncts to
conventional therapies. Evidence is insu5 cient to support the antidepressant bene, t of
dehydroepiandrosterone, inositol, folate, and sa7ron. Only kava has high-quality evidence for use in
the treatment of anxiety disorders, and its use is discouraged because of safety concerns. There is
preliminary supportive evidence for valerian and inositol treatment of anxiety, but SJW and
passion; ower have achieved little research support. Melatonin is likely to be useful in treating
delayed sleep phase, jet lag, or shift work, but there is little evidence for the bene, t of valerian
compared with placebo. There are currently no evidence-supported CAM treatments for ADHD (zinc
and omega-3 fatty acids are reviewed).
• Complementary and alternative medicine • Depression • Anxiety • Insomnia •
Attentiondeficit/hyperactivity disorder (ADHD) • Dietary supplements
Key points for practice
There is strong evidence to support the use of St John’s wort (SJW) for mild to moderate depression in
aadults (evidence category A)
Omega-3 fatty acids and S-adenosyl-l-methionine may have benefit as adjuncts to standard
pharmacologic therapy for depression (evidence category B)
Although kava seems to have anxiolytic benefit, safety concerns outweigh its usefulness at the present
time (evidence category B)
There is evidence to support the use of melatonin supplements in individuals with delayed sleep phase or
jet lag, or in shift workers (evidence category B)
There are no evidence-supported supplements for the treatment of attention-deficit/hyperactivity
disorder (evidence category B)
a Level A, large, high-quality, double-blind, randomized controlled trials; level B, smaller trials,insu5 ciently powered trials, single-blinded trials, cohort, and case-controlled studies; level C, expert
opinion or consensus
Mental health disorders are prevalent in primary care, a7ecting up to 30% of patients, and account for
a great degree of disability. Patients su7ering from mental health conditions use a disproportionate
amount of conventional medical resources and often have di5 culty achieving full remission of their
psychological conditions. Many (up to 50%) turn to complementary and alternative medicine (CAM)
1interventions attempting to ease their distress, although this number seems to have dropped between
22002 and 2007. The use of CAM modalities has been found to be especially common among patients
1with mental health conditions.
Patients choose CAM modalities for a variety of reasons including a preference for natural therapies, the
fear of addiction to conventional mental health medications, congruence with their lifestyle choices, and
lack of satisfaction with conventional treatment options. Patients may also choose nonstandard treatments
because of financial barriers to accessing conventional care.
Biologically based therapies (herbs, supplements, dietary manipulations) are the most commonly used
3,4CAM therapy, with an estimated $23 billion in expenditure in 2007. This review focuses on biologically
based therapies with the highest quality evidence (either supportive or negative), the most promise, or the
greatest amount of popular recognition as possible treatments for depression, anxiety, sleep disturbance,
and attention-de, cit/hyperactivity disorder (ADHD). The evidence for the use of each supplement for a
particular indication is reviewed, with any existing systematic reviews or meta-analyses being highlighted.
Much of the evidence for the use of CAM products to treat behavioral health conditions comes in the form
of small, open-label, inadequately controlled trials or case studies. Comparisons of CAM products with
adequate doses of proven conventional medications are rare.
Although optimal doses for many CAM products have not been established, the most frequently
investigated dosages are noted in the tables for each herb/supplement discussed. These dosages are not
provided as an endorsement in cases of products lacking evidence of e5 cacy, but as an aid to physicians
in counseling their patients who may choose to use the (sometimes) unproven therapies. Considerations of
purity and bioavailability are not addressed, as these vary by manufacturer. Contraindications and
drugdrug interactions are often theoretic or the evidence is poor, but they are noted where relevant.
A recent study suggests that 10% of primary care patients meet criteria for major depression or
5dysthymia. These conditions create signi, cant disease burden and many patients experience di5 culty
, nding adequate treatment. In one study of women with depression, 54% had used 1 of 3 CAM modalities
(vitamins, dietary supplements, or manual therapies such as acupressure, massage, and chiropractic) to
6treat their mood during the past year. The evidence base for several herbal remedies and dietary
supplements promoted for the treatment of depression is reviewed in this article and summarized in Table
1. Nonsupplement CAM modalities for depression are summarized in Table 2.
Table 1 Herbs and supplements commonly used in the treatment of depressionTable 2 Nonsupplement CAM modalities for depression
Treatment Modality/Conclusion aCategory
Verum acupuncture has not yet been shown to be superior to nonspecific acupuncture or B
sham acupuncture in the treatment of depression111
There is some evidence that exercise interventions can produce significant improvement in Bdepression and reduce the risk of relapse, however, nonspecific effects (eg, activation,
attention) may play a role in these findings.112,113 Until further study, exercise may be
best used as an adjunctive intervention
There is no clear evidence of benefit for mindfulness or other meditation procedures in the B
treatment of depression114
Yoga has garnered initial evidence for treatment of depression, but further study is B
Homeopathy for depression has not been supported by the high-quality research that would B
be necessary to counteract its biologic implausibility116
Progressive muscle relaxation training may provide a benefit over no treatment, but is A
not as effective as conventional medications or cognitive behavioral therapy in treating
a Level A, large, high-quality, double-blind, randomized controlled trials; level B, smaller trials,
insu5 ciently powered trials, single-blinded trials, cohort, and case-controlled studies; level C, expert
opinion or consensus.
St John’s Wort
St John’s wort (SJW; Hypericum perforatum) has a long history of use as an antidepressant in Europe, and
its popularity in the United States has grown signi, cantly in recent decades. There is pharmacokinetic
7evidence for hypericum as a serotonin, dopamine, and norepinephrine reuptake inhibitor. It may also
have weak monoamine oxidase inhibiting qualities. Although some constituent substances (such as
hypericin and hyperforin) have been shown to have antidepressant activity, the total extract seems to be
8more effective than any isolated part.
The clinical evidence supporting the e5 cacy of SJW in the treatment of mild to moderate depression is
9now very strong. Although there were a few high pro, le randomized controlled trials (RCTs) completed
10,11in psychiatric care settings that did not support the antidepressant bene, t of SJW (n = 540), a 2008
Cochrane Review of 29 randomized, double-blind, placebo-controlled trials (n = 5489; 18 comparisons
with placebo, 17 comparisons with conventional antidepressants) concluded that SJW has similar e5 cacy
8to standard antidepressants and is superior to placebo in the treatment of major depression. It was noted
by the reviewers that higher-quality trials yielded slightly less positive results, and the conventional
antidepressant dosages were typically at the lower end of currently recommended dose ranges. SJW is
believed to be less e7ective in severe chronic depression, but is able to prevent relapse in patients who
9achieve remission. The extant literature suggests that patients taking SJW may have fewer side e7ects
12than those taking standard antidepressants.
13SJW is usually well tolerated and has a side e7ect pro, le similar to placebo. The most common
14complaints include gastrointestinal distress, dry mouth, dizziness, and confusion. Other adverse e7ects
include agitation, irritability, sexual dysfunction, skin rash, paresthesia, and hypoglycemia. Like
conventional antidepressants, SJW can provoke mania/hypomania in patients with bipolar disorder. In
patients prone to mania, SJW should not be used without a mood stabilizer. Photosensitivity occurs rarely,
and may be decreased by using sunscreens and sun protection strategies.
SJW has several important medication interactions, most of which are caused by increased cytochrome
P450 activity. Long-term treatment with SJW can reduce the clinical e5 cacy or increase doserequirements for drugs metabolized by the cytochrome P450 system. This includes half or more of
currently marketed medications, including oral contraceptive pills, digoxin, and warfarin. Human
immunode, ciency virus (HIV)-positive patients taking antiretroviral medications, patients who have
cancer receiving chemotherapy, and transplant patients taking cyclosporine should not be treated with
SJW. Serotonin syndrome may occur with SJW overdose, and when SJW is combined with a selective
15serotonin reuptake inhibitor (SSRI), nefazodone, or triptans.
Omega-3 Fatty Acids
The omega-3 fatty acids are nutritionally essential, naturally occurring lipids contained in , sh oil and
certain plants (eg, ; ax/linseed). Used for several indications, , sh oil/omega-3 and ; axseed oil were
2among the top herbal/supplement products used by Americans in 2007. Fish oil/omega-3 is the number
1 supplement among individuals using nonmineral/nonvitamin natural products (37.4%). Flaxseed
products rank fourth in popularity, at 15.9%. Several studies have reported associations between a
16country’s , sh consumption and rates of depression, including postpartum depression. Epidemiologic
17studies have also linked increased personal , sh consumption to decreased risk of depression. There have
been numerous proposed methods of action for the omega-3 fatty acids in mood disorders. Omega-3 fatty
acids may inhibit intracellular signal transduction in a way similar to that of established mood stabilizers,
18inhibit the movement of calcium ions, and/or reduce protein kinase C activity. One of the most popular
hypotheses is that in; ammation may contribute to major depression, and omega-3 fatty acids may
18suppress the overactivity of inflammatory pathways.
There have been at least 10 randomized, double-blind, placebo-controlled trials of the e7ect of omega-3
supplementation on unipolar depression (n = 467). Six of these studies found omega-3 monotherapy or
19-23adjunctive therapy to be signi, cantly better than placebo for unipolar depression. Those studies
, nding a bene, t of omega-3s over placebo all used high eicosapentanoic acid (EPA) to docosahexanoic
acid (DHA) ratio formulations (EPA/DHA 2:1). Although early research into omega-3 treatment of
depression seems promising, at the present time, supplementation of standard antidepressant therapy
(rather than replacement) may be the best evidence-based choice.
The common adverse e7ects of gastrointestinal distress and , shy aftertaste may be reduced by taking
the supplement with food, decreasing the total daily dosage, choosing higher-quality supplements, taking
the medication at bedtime, or freezing the capsules before ingestion. Patients on anticoagulant therapy
should be monitored for bleeding/bruising, and may require decreased anticoagulant doses.
Folate is a water-soluble essential vitamin (B ). Folate de, ciency has been associated with depressive9
symptoms in patients with depression and in the general population, and may be predictive of poor
24response to antidepressant treatment. Folate depletion can often be caused by medications including
many anticonvulsants, oral contraceptives, metformin, lithium, and methotrexate. Depletion of folate can
also result from pregnancy, smoking, alcoholism, poor nutrition, and gastrointestinal disorders. Much of
the research examining the role of folate de, ciency in depression was conducted before the mandated
folic acid forti, cation of US grain products (in 1998), which has dramatically decreased the population
prevalence of low folate. Because of the decline in overall folate de, ciency, recent research e7orts have
examined the possible antidepressant bene, ts of folate supplementation, even to supraphysiologic levels.
Although the rationale for folate supplementation is strong, high-quality evidence is limited. One RCT has
demonstrated a signi, cant bene, t of folic acid supplementation (in individuals without folate de, ciency)
25as an adjunct to standard antidepressant treatment. Folate monotherapy was equivalent to 100 mg26trazodone (which is An open-label trial of adjunctive folinic acid (leucovorin) showed a modest
27response in improving the depression scores of SSRI nonresponders. In summary, limited evidence
suggests folate augmentation of conventional antidepressants may improve patient outcomes. Folic acid
13seems to be safe and well tolerated at the recommended supplementation levels (<1000> High-dose
13folic acid should be avoided as it may decrease natural killer cell effectiveness.
S-Adenosyl-l-methionine (SAMe) is a naturally occurring substance found throughout the body and brain.
It is synthesized through the 1-carbon cycle, which also involves vitamin B12 and folate. SAMe is involved
in monoamine and melatonin synthesis, and low central nervous system (CNS) levels of SAMe have been
28documented in depression. It has been widely prescribed in Europe for more than 30 years. A 2002
Agency for Healthcare Research and Quality meta-analysis of 26 SAMe studies concluded that treatment
29with SAMe is likely to lead to moderate reductions in clinical depression. There have been at least 11
randomized, double-blind controlled studies (N >1050) examining the use of SAM-e (oral, intravenous,
and intramuscular forms) in the treatment of major depression. At least 6 randomized placebo-controlled
30,31studies have found SAMe to be superior to placebo (sample sizes ranged from 40 to 100 per study).
Most head-to-head comparisons with tricyclic antidepressants have found SAMe to be comparable in
30-33e5 cacy with tricyclic antidepressants. No direct comparisons with SSRIs have been published, but
there is some initial evidence that SAMe may be an e7ective adjunctive medication for patients partially
34responding or nonresponding to SSRI monotherapy. SAMe may have an earlier onset of e7ectiveness
30-32compared with antidepressants and may speed the onset of antidepressant action when used
35,36adjunctively. SAMe is well tolerated, with mild side e7ects such as decreased appetite, insomnia, dry
13mouth, and nervousness. There is no apparent toxicity.
Inositol (sometimes referred to as vitamin B ) is an isomer of glucose, found in cell membranes, which8
occurs naturally in numerous foods (nuts, legumes, whole grains). It was noted long ago that patients who
are clinically depressed have decreased levels of inositol in cerebrospinal ; uid (CSF), which led to the
37hypothesis that inositol supplementation may be bene, cial for mood disorders. After an initial, positive
38pilot study, Levine and colleagues then completed a double-blind randomized study of 12 g of inositol
daily versus placebo for depression. By 1 month of treatment, the inositol group showed signi, cantly
greater mood improvement than the placebo group. Studies examining the possibility of SSRI
augmentation with inositol did not , nd a bene, t for this combination, which may suggest similar
39mechanisms of action for these substances. Despite intriguing preliminary studies, the use of inositol as
40a , rst-line therapy for depression cannot yet be supported, and further studies of inositol’s use seem to
be in short supply. Inositol seems to be fairly well tolerated, with mild gastrointestinal distress being the
most prominent adverse reaction. At higher dosages, sleepiness, headache, and dizziness have also been
Saffron (Crocus sativus) is a highly expensive, coveted cooking spice and a traditional Persian remedy used
13for a large number of conditions, including depression. No mechanism of action for sa7ron has been
speci, ed. Several small trials have been published (from 1 research group) testing the e7ectiveness of
41,42sa7ron for major depression. Two small 6-week double-blind trials with a total of 80 participants
compared a 30 mg/d capsule of sa7ron with placebo. In each of these trials, the sa7ron group receivedsignificantly greater antidepressant benefit (P<_.00129_. three="" additional="" randomized=""
placebocontrolled="" studies="" comparing="" sa7ron="" capsules="" with="" low="" doses="" of=""
43,44 45; uoxetine="" _28_20=""> and imipramine (100 mg/d) have also been conducted by this
research group. In each of these short trials (6 and 8 weeks) sa7ron was found to have equivalent bene, t
to the conventional antidepressants. Although the research evidence does not yet support sa7ron as a ,
rstline depression treatment, these promising early results deserve replication with larger sample sizes and
greater duration, and using adequate or ; exible-dose comparators. Sa7ron seems to be well tolerated in
the doses used for depression. Side e7ects were generally mild and included drowsiness, gastrointestinal
distress, and anxiety.
Anxiety is a common complaint in primary care settings, with approximately 7% of US adults su7ering
anxiety to the degree that intervention is required. Among American consumers of
nonvitamin/nonmineral dietary supplements, 2.8% are using the product to treat anxiety, the , fth most
2popular indication for use (behind back, neck and joint pain, and arthritis). The evidence for the most
popular herbal preparations taken for anxiety is discussed in the following sections, and additional
information on these, and other, supplements is summarized in Table 3. Nonherb/nonsupplement CAM
modalities for treating anxiety are reviewed in Table 4.
Table 3 Herbs and supplements commonly used in the treatment of anxiety
Table 4 Nonherb/supplement CAM modalities for the treatment of anxiety
Modality/Conclusion aCategory
Relaxation training (meditation, progressive muscle relaxation) is beneficial in the Atreatment of anxiety121
Acupuncture has not yet been shown to be superior to sham or nonspecific acupuncture in B
the treatment of anxiety114
Homeopathy has not been shown to be superior to placebo in the treatment of anxiety in B
an adequately powered, placebo-controlled, randomized trial with appropriate blinding122
is beneficial as an anxiety intervention123 BAerobic exercise
a Level A, large, high-quality, double-blind, randomized controlled trials; level B, smaller trials,
insu5 ciently powered trials, single-blinded trials, cohort, and case-controlled studies; level C, expert
opinion or consensus.
St John’s Wort
Because of the popularity of SJW in the treatment of depression, its use for anxiety disorders has also been
proposed. Compared with the literature examining the e5 cacy of SJW for depression, the anxiety
literature is extremely sparse. Several published case reports have supported the e5 cacy of SJW in the
46,47treatment of generalized anxiety disorder (GAD). However, a double-blind placebo-controlled pilot
investigation (n = 28) of a combination of SJW and kava in the treatment of anxious depression failed to
48, nd signi, cant anxiolytic bene, t of the combined herbal supplement over placebo. One small (n =
12), open-label study examined the use of SJW in the treatment of obsessive compulsive disorder (OCD)
49and found that the supplement decreased symptoms compared with baseline. This study did not o7er a
placebo comparison, so it was replicated in a subsequent, larger (n = 60) double-blind RCT by the same
50research group. The second trial failed to , nd symptom improvement in those patients randomized to
SJW over those given a matching placebo. SJW also failed to surpass the e7ect of placebo as a treatment
51of social phobia in a small RCT (n = 40). These results suggest that, despite the pharmacokinetic
rationales for the use of SJW in anxiety disorders, patients should be advised to pursue evidence-based
therapies to combat anxiety rather than this supplement. As with some conventional antidepressants, SJW
can be stimulating to some patients. This side e7ect can be particularly troublesome to patients su7ering
from anxiety. Patients with depression and comorbid anxiety who are determined to pursue treatment
with SJW should be advised to begin with lower doses of the supplement and increase slowly to prevent
the potential exacerbation of their anxiety.
Valerian (Valeriana o2 cinalis) is a pink-; owered perennial. The roots are believed to have properties
similar to the benzodiazepines or barbiturates. Valerian has an extensive history of use around the world
to treat sleep disturbance and anxiety, but little scienti, c e7ort has been spent evaluating its anxiolytic
properties. Although there is preliminary evidence that valerian can reduce self-rated stress in healthy
volunteers exposed to stress-inducing research protocols, there have been few examinations of valerian for
52,53 54diagnosed anxiety disorders. One pilot study (n = 36) examined the e5 cacy of valerian in the
treatment of GAD, compared with diazepam and placebo. Following 4 weeks of treatments, each of the 3
groups showed a signi, cant decline in clinician-rated global anxiety, with no signi, cant di7erences on
this outcome measure between groups. The valerian and diazepam groups did outperform placebo by
signi, cantly reducing psychic (nonsomatic) symptoms of anxiety. Because of the small size of this study
and the lack of di7erence in the main outcome measure, no conclusions about valerian’s e5 cacy can be
drawn without replication and extension of the research. Valerian is well tolerated, with minimal side
e7ects such as gastrointestinal distress, headache, dizziness, and morning hangover (at doses >450mg/night) being most common. Valerian may have additive e7ects when taken with other CNS
Kava preparations are derived from the root and rhizomes of a pepper plant (Piper methysticum)
56indigenous to the South Paci, c. A 2003 Cochrane report and a separate, independent meta-analysis of
57studies using the kava extract WS1490 both suggest that kava is more e7ective for mild anxiety than
placebo. These results were also found in a recent, high-quality double-blind RCT (n = 60) in which a
crossover design was used to evaluate the use of aqueous kava extract in the treatment of patients
58presenting with at least 1 month of excessive worry. This trial excluded placebo responders (identi, ed
using a 1-week placebo run-in phase). In this brief trial (1 week per intervention phase), kava was found
to signi, cantly decrease participants’ anxiety scores relative to placebo. However, research comparing
kava with standard antidepressants has had mixed results. In 1 double-blind RCT (n = 129) for the
treatment of GAD, kava compared favorably with a very low dose of buspirone (10 mg/d) and opipramol
59(100 mg/d), an anxiolytic related to the tricyclic antidepressants. Unfortunately, this trial did not
include a placebo control. A pooled analysis of 3 small RCTs (total n = 64) comparing kava with placebo
and with venlafaxine in the treatment of GAD documented no signi, cant di7erence between any of the
The most frequently noted adverse e7ects of kava include headache and gastrointestinal complaints.
Kava can potentiate the e7ects of CNS depressants, and should be used cautiously with conventional
sedative hypnotics and anxiolytics. There is evidence that excessive kava ingestion (>450 mg/d) for
61,62extended periods may be associated with liver toxicity. In light of these concerns, the US Food and
Drug Administration (FDA) and Centers for Disease Control have warned consumers of the potential for
liver-related injuries caused by kava, as has Health Canada. Several other countries (Switzerland,
Germany, France, the Netherlands, and the United Kingdom) have withdrawn kava products from the
market. The World Health Organization has suggested that the hepatotoxicity linked to kava formulations
may have been because of the use of aerial parts or root or stem peelings of the plant (rather than the
63peeled root) in the preparations, or related to the method of extraction (using ethanol or acetone). This
conclusion has led to some renewed interest in investigating aqueously derived kava extracts from peeled
rootstock. The use of kava by individuals taking other possibly hepatotoxic medications, or those with
known liver disease, should be strongly discouraged. Anyone using kava should do so under the
supervision of a physician, and regular monitoring of liver functioning should be conducted. In summary,
although high-quality evidence suggests kava may be bene, cial for anxiety, safety concerns outweigh its
potential benefits at this time.
Because of the crossover e7ectiveness of the SSRIs in treating anxiety disorders, inositol has garnered
interest as an anxiety treatment. Inositol has been shown in double-blind, placebo-controlled, crossover
64trials to be superior to placebo and equal to 150 mg ; uvoxamine (in a trial that was possibly too
65brief) for the treatment of panic disorder. The results of 1 small-scale double-blind, placebo-controlled
study of inositol for the treatment of OCD suggest greater improvement of some OCD symptoms in patients
66taking inositol versus placebo. As with the treatment of depression described previously, inositol
augmentation of SSRIs has not been found to be bene, cial in treating OCD patients who received less than
67full bene, t from conventional antidepressants, and SSRI nonresponders also tend to be unresponsive to
66inositol. Despite the initial positive results, which largely emanated from 1 set of investigators, interest3
in the scienti, c investigation of inositol for psychiatric indications seems to be waning. The most
prominent side e7ect of inositol is gastrointestinal distress (; atulence, nausea). At higher dosages,
sleepiness, headache, and dizziness have also been reported. The safety of long-term, high-dose inositol
consumption has not been established.
Passi ora incarnata is 1 of several hundred plants of the Passi; oraceae family, which is native to the
13Americas. It is used as a folk remedy for anxiety, insomnia, and gastrointestinal distress. A component
13of passion; ower (apigenin) is believed to bind to the central benzodiazepine receptors. Passion; ower
was, in the past, approved for over-the-counter sale in the United States for the treatment of insomnia, but
was withdrawn in 1978 because of lack of safety and e5 cacy data. Two double-blind RCTs (n = 198,
68,69total) of passion; ower for anxiety are available. One study compared passion; ower with oxazolam
6930 mg (Serax; a long-acting benzodiazepine). The second trial compared it with mexazolam.
Passion; ower could not be di7erentiated from the benzodiazepines in these studies. However, the degree
to which this equivalence was attributable to small sample sizes versus similar action cannot be
70determined. No published trials are available that compare passion; ower with placebo or with
conventional antidepressants. Passion; ower is generally well tolerated. Side e7ects can include dizziness,
ataxia, and confusion. Based on the pharmacologic pro, le of the plant, theoretic adverse e7ects could
13include CNS depression and bradycardia.
71One-third of adults in the United States report di5 culties with sleep onset or maintenance. In addition
to insomnia secondary to psychiatric disturbance (eg, a7ective disorders, GAD), sleep di5 culties can be
caused by misalignment between the circadian cycle and the preferred sleep-wake cycle as a result of the
demands of shift work or travel (eg, jet lag). In most industrialized nations, up to 20% of the population is
72engaged in nighttime employment. Inadequate sleep is associated with increased risk of industrial and
73,74vehicular accidents and health problems including type 2 diabetes, heart disease, and obesity.
Because of the problems of addiction, habituation, and withdrawal with some of the conventional
pharmacologic treatments for insomnia, interest in possible alternative treatments is high; more than 1
75million Americans choose CAM modalities to promote sleep each year. Insomnia is the tenth most
popular indication for the use of nonvitamin/nonmineral dietary supplements (accounting for 1.4% of all
2users). Table 5 summarizes information about the herbs/supplements used to treatment insomnia.
Table 5 Herbs and supplements commonly used in the treatment of insomniaValerian
Valerian (Valeriana o2 cinalis) is a herb widely touted as bene, cial for sleep. It is thought that
components within valerian (such as valerenic acid) may decrease CNS activity by inhibiting the
breakdown of γ-aminobutyric acid (GABA), or by binding to GABA-A receptors and increasing GABA
76release. Recent comprehensive reviews of the published research have either branded the e5 cacy of
77,78valerian for sleep complaints as inconclusive or stated that its clinical e5 cacy is no greater than
79 79placebo. In the most recent review, Taibi and colleagues identi, ed 37 studies of valerian or valerian
combined with hops, lemonbalm, or passion; ower for the improvement of sleep (some studies used
healthy participants without identi, ed sleep di5 culties). The results of this review cast doubt on the
e5 cacy of valerian or valerian combinations to improve subjective or objective sleep parameters. Of
particular importance is the investigators’ observation that the highest quality studies were even less likely
to , nd a statistical bene, t for valerian over placebo. Valerian has been extremely safe in clinical trials,
79with a side e7ect rate similar to placebo. As previously noted, the most common adverse e7ects seem to
be gastrointestinal distress, headache, dizziness, and morning hangover (at high doses).
Melatonin (N-acetyl-5-methoxytryptamine) is a neurohormone produced by the pineal gland, which is
largely responsible for regulating circadian rhythms. It is also a popular dietary supplement, used by 4.6%
2of US adults taking a nonvitamin/nonmineral dietary product. Endogenous melatonin is most heavily
produced at night, and the increased production of melatonin is temporally related to increased sleepiness.
A review of 14, largely moderate quality, double-blind RCTs (n = 425 total) of melatonin for the
treatment of primary insomnia concluded that melatonin decreases sleep onset latency by a statistically
80signi, cant, but clinically insigni, cant 12 minutes compared with placebo. A subanalysis (n = 30)
including only those patients with delayed sleep phase syndrome (chronically shifted sleep occurring from
early morning to late morning; eg, 3 am to 11 am) showed much greater bene, t (40 minute improvementin sleep onset latency). Elderly patients may bene, t from greater sleep e5 ciency (percentage of time in
bed spent sleeping) through the use of melatonin; however, younger adults do not. For patients with
secondary insomnia (as a result of psychiatric/medical/neurologic disorders), exogenous melatonin does
not decrease sleep onset latency, but may improve sleep e5 ciency to a statistically but not clinically
81signi, cant degree (10 minute di7erence in sleep time in a meta-analysis of 6 RCTs; n = 97). A 2006
meta-analysis (9 RCTs; n = 427) published in the British Medical Journal examining the e5 cacy of
melatonin in easing sleep disorders related to sleep restriction (jet lag, shift work) suggested a
nonsigni, cant trend toward decreased sleep onset latency with the use of melatonin, but no improvement
82in sleep efficiency. One di5 culty in assessing the true e7ect of melatonin is that not all of the studies on
shift work controlled for environmental features such as light (which also serves to set circadian rhythms).
A Cochrane Review that speci, cally examined the e7ect of melatonin on symptoms of jet lag in
individuals crossing 5 or more time zones suggests a strong positive bene, t of melatonin on sleep onset
83latency and daytime functioning. In conclusion, at the present time, the strongest evidence for
melatonin seems to be for individuals in need of assistance shifting their circadian sleep period (eg,
individuals with jet lag or delayed sleep phase) rather than those su7ering from pure di5 culty with sleep
onset. Short-term use of exogenous melatonin seems to be safe and well tolerated. Adverse e7ects tend to
82be mild (nausea, headache, dizziness) and infrequent (<_1025_2c_ rates="" similar="" to="">
Other CAM Modalities
In addition to herbal remedies, acupuncture and mindfulness-based stress reduction have been proposed
as treatments for sleep disturbance. The extant literature on these modalities is not yet of su5 cient scale,
84,85quantity, or rigor to allow them to be recommended for insomnia.
ADHD is a behavioral disorder frequently seen in primary care settings. It is estimated that 8% to 10% of
86,87children and 4% of adults meet diagnostic criteria for ADHD. There is considerable dissatisfaction
among parents regarding the use of psychostimulants because of their side e7ects and the stigma
associated with the use of these medications. ADHD is the , fth most common reason for the use of dietary
2supplements in children. One study conducted in 1999 found that 54% of parents reported using CAM
modalities such as megavitamins and dietary restrictions in the treatment of their child’s attention
88difficulties. Few parents in this study had discussed their use of CAM with their child’s physician (11%).
Herbs and supplements commonly used for ADHD are summarized in Table 6, and nonsupplement CAM
modalities are reviewed in Table 7.
Table 6 Herbs and supplements commonly used in the treatment of ADHDTable 7 Nonherb/supplement CAM modalities for the treatment of ADHD
Modality/Conclusion aCategory
Elimination (Feingold) diets may be useful in a small subset of children with food B
is not effective in altering the symptoms of ADHD126 ASugar elimination
Electroencephalographic (EEG) neurofeedback (biofeedback procedure training patients B
to maximize “relaxed and alert” activity on EEG) is promising, but not yet proven as a
treatment of ADHD because of the significant methodological weaknesses in the
has not been shown to be effective in treating ADHD128 BHomeopathy
a Level A, large, high-quality, double-blind, randomized controlled trials; level B, smaller trials,
insu5 ciently powered trials, single-blinded trials, cohort, and case-controlled studies; level C, expert
opinion or consensus.
Zinc is an essential mineral involved in numerous biologic processes including CNS functioning and the
modulation of glutamatergic neurons in the brain. Zinc’s role in dopamine and serotonin neurotransmitter
synthesis may account for its potential bene, t to patients with ADHD. It has been shown that children
89diagnosed with ADHD have lower zinc tissue concentrations than controls, and that response to
90stimulant medication may be hampered by zinc de, ciency. One double-blind study of zinc sulfate
monotherapy for ADHD (n = 400) that used randomized assignment to groups and a placebo
comparison, found signi, cant bene, t of zinc over placebo in treating the hyperactive, impulsive, and
91social skills de, ciency symptoms of ADHD, but not the attentional symptoms. One caveat is that this92study and a pilot study , nding bene, t of zinc augmentation in children treated with methylphenidate,
were conducted in countries (Turkey, Iran) in which zinc-depleted soils are more common than in the
United States, promoting zinc-de, cient diets. Additional well-controlled trials in westernized countries are
needed before the benefits of zinc as a treatment of ADHD can be generalized.
Zinc sulfate is typically well tolerated and side e7ects are generally mild, including gastrointestinal
distress and metallic taste in the mouth. Excessive zinc intake (>10 g) or chronic use of extreme amounts
(450–1600 mg daily) can cause sideroblastic anemia, copper de, ciency, or death. Patients taking
quinolone or tetracycline antibiotics should be encouraged to separate the ingestion of zinc from the
ingestion of the antibiotic by at least 2 hours to reduce the possibility of decreased antibiotic absorption.
Omega-3 Fatty Acids
Omega-3 polyunsaturated fatty acids have received attention for the treatment of several physical and
mental health conditions, including depression and ADHD. Omega-3 fatty acids have been described as
critical to dopamine-driven appropriate frontal lobe (executive) functioning, which has been a noted
93problem in ADHD. Children with ADHD have been noted to have decreased blood concentrations of
94omega-3 fatty acids compared with matched control children. Three double-blind placebo-controlled
studies have shown nominal improvements in ADHD symptoms with omega-3 supplementation over
93,95,96placebo in school-aged children. Several additional studies have produced equivocal
97-100 93results. Only 1 of these studies used the type of high EPA formulation found to be most e7ective
in the depression literature (summarized earlier). A recent systematic review concludes that evidence is
101lacking for a “valid, robust clinical e7ect” for omega-3 supplementation on ADHD symptoms. In
summary, although omega-3 supplementation is safe and relatively easily accomplished, it should not be
recommended to patients as an alternative to proven conventional therapies.
Implications for practice
There is strong evidence to support the use of SJW for mild to moderate depression in adults, with e5 cacy
equivalent to prescription antidepressants and fewer reported side e7ects. Lesser, but promising, evidence
exists to support the use of omega-3 fatty acids and SAMe as potential adjuncts to standard pharmacologic
therapy for depression. Although some early trials with dehydroepiandrosterone, inositol, folate, and
sa7ron have suggested an antidepressant bene, t, the evidence is presently insu5 cient to support their
clinical use, and further investigation is needed.
High-quality evidence exists to support the bene, t of kava for mild anxiety, but major concerns about
hepatotoxicity risk have resulted in FDA warnings that kava should be avoided. Studies of valerian and
inositol have shown decreased psychiatric symptomatology compared with placebo; however, the
evidence is insu5 cient to draw de, nitive conclusions, and further study is necessary. The value of SJW
and passionflower in the treatment of anxiety disorders has not been supported by RCTs.
Extensive study and published reviews of melatonin data on sleep have yielded strong evidence of
bene, t in individuals with delayed sleep phase, jet lag, or shift work, by altering the circadian sleep cycle.
There is some evidence that it may be bene, cial as a sleep agent in geriatric patients, and it is well suited
to that population because of its favorable side e7ect pro, le. Although also broadly studied and found to
be generally safe, there is minimal high-quality evidence to support the use of valerian over placebo in the
treatment of insomnia. When discontinued, valerian should be slowly tapered because of withdrawal risks.
Research demonstrating bene, t from zinc supplementation for ADHD has primarily been conducted in
Middle Eastern countries predisposed to zinc-de, cient diets. Additional investigation is required before
conclusions can be drawn about its usefulness elsewhere. Although there is a theoretic bene, t of omega-3fatty acids for ADHD, it has not yet been substantiated in trials.
1. R.C. Kessler, J. Soukoup, R.B. Davis, et al. The use of complementary and alternative therapies to treat
anxiety and depression in the United States. Am J Psychiatry. 2001;158:289-294.
2. Barnes PM, Bloom B, Nahin R. CDC National Health Statistics Report #12. Complementary and
alternative medicine use among adults and children: United States, 2007. Available at:
http://www.nccam.nih.gov/news/2008/nhsr12.pdf. Accessed March 16, 2010.
3. NIH state-of-the-science conference statement on multivitamin/mineral supplements and chronic disease
prevention. Ann Intern Med. 2006;145:364-371.
4. National Center for Complementary and Alternative Medicine (NCCAM). The use of complementary and
alternative medicine in the United States. Based upon National Center for Health Statistics National
Health Interview Survey 2007. Available at: http://nccam.nih.gov/news/camsurvey_fs1.htm Accessed
June 15, 2009
5. J.L. Jackson, M. Passamonti, K. Kroenke. Outcome and impact of mental disorders in primary care at 5
years. Psychosom Med. 2007;69:270-276.
6. P. Wu, C. Fuller, X.H. Liu, et al. Use of complementary and alternative medicine among women with
depression: results of a national survey. Psychiatr Serv. 2007;58(3):349-356.
7. W. Muller, M. Rolli, U. Schafer. Effects of hypericum extract (Li 160) in biochemical models of
antidepressant activity. Pharmacopsychiatry. 1997;30(2):102-107.
8. Linde K, Berner MM, Kriston L. St John’s wort for major depression. Cochrane Database Syst Rev 2008; 4.
Art No:CD000448.
9. A.A. Nierenberg, H.G. Lund, D. Mischoulon. St. John’s wort: a critical evaluation of the evidence for
antidepressant effects. In: D. Mischoulon, J.F. Rosenbaum, editors. Natural medications for psychiatric
disorders. 2nd edition. Philadelphia: Lippincott Williams, Wilkins; 2008:27-38.
10. R.C. Shelton, M.B. Keller, A. Gelenberg, et al. Effectiveness of St. John’s wort in major depression. A
randomized controlled trial. JAMA. 2001;285:1978-1986.
11. Hypericum Depression Trial Study Group. Effect of Hypericum perforatum (St John’s wort) in major
depressive disorder. A randomized controlled trial. JAMA. 2002;287:1807-1814.
12. E. Schrader. Equivalence of St. John’s wort extract (Ze117) and fluoxetine: a randomized controlled
study in mild-moderate depression. Int Clin Psychopharmacol. 2000;15(2):61-68.
13. Natural Medicines Comprehensive Database. Available at: http://www.naturaldatabase.com Accessed
June 15, 2009
14. Woelk H,. Burkhard G, Gruenwald J. Evaluation of the benefits and risks of the Hypericum extract LI160
based on a drug monitoring study with 3250 patients. Nervenheilkunde 1993;12:308–13. Available at:
http://www.schattauer.de/en/magazine/subject-areas/journals-a-z/nervenheilkunde.html. Accessed
February 5, 2009.
15. G. Di Carlo, F. Borrelli, E. Ernst, et al. St John’s wort: Prozac from the plant kingdom. Trends Pharmacol
Sci. 2001;22:292-297.
16. J.R. Hibbeln. Fish consumption and major depression. Lancet. 1998;351:1213.
17. A. Tanskanen, J.R. Hibbeln, J. Hintikka, et al. Fish consumption, depression, and suicidality in a general
population. Arch Gen Psychiatry. 2001;58:512-513.
18. A.L. Stoll. Omega-3 fatty acids in mood disorders: a review of neurobiologic and clinical actions. In: D.
Mischoulon, J.F. Rosenbaum, editors. Natural medications for psychiatric disorders. 2nd edition.
Philadelphia: Lippincott Williams, Wilkins; 2008:39-67. 19. M. Peet, D.F. Horrobin. A dose-ranging study of the effects of ethyleicosapentaenoate in patients with
ongoing depression despite apparently adequate treatment with standard drugs. Arch Gen Psychiatry.
20. B. Nemets, Z. Stahl, R.H. Belmaker. Addition of omega-3 fatty acid to maintenance medication treatment
for recurrent unipolar depressive disorder. Am J Psychiatry. 2002;159:477-479.
21. K.P. Su, S.Y. Huang, C.C. Chiu, et al. Omega-3 fatty acids in major depressive disorder. A preliminary
double-blind placebo-controlled trial. Eur Neuropsychopharmacol. 2003;13:267-271.
22. H. Nemets, B. Nemets, A. Apter, et al. Omega-3 treatment of childhood depression: a controlled,
doubleblind pilot study. Am J Psychiatry. 2006;163:1098-1100.
23. Y. Osher, R.H. Belmaker. Omega-3 fatty acids in depression: a review of three studies. CNS Neurosci Ther.
24. J.E. Alpert, G.I. Papakostas, D. Mischoulon. One-carbon metabolism and the treatment of depression:
roles of S-adenosyl-L-methionine and folate. In: D. Mischoulon, J.F. Rosenbaum, editors. Natural
medications for psychiatric disorders. 2nd edition. Philadelphia: Lippincott Williams, Wilkins; 2008:68-83.
25. A. Coppen, J. Bailey. Enhancement of the antidepressant action of fluoxetine by folic acid: a
randomised, placebo controlled trial. J Affect Disord. 2000;60:121-130.
26. M.J. Taylor, S.M. Carney, G.M. Goodwin, et al. Folate for depressive disorders: systematic review and
meta-analysis of randomized controlled trials. J Psychopharmacol. 2004;18:251-256.
27. J.E. Alpert, D. Mischoulon, G.E. Rubenstein, et al. Folinic acid (leucovorin) as an adjunctive treatment
for SSRI-refractory depression. Ann Clin Psychiatry. 2002;14:33-38.
28. T. Bottiglieri, P. Godfrey, T. Flynn, et al. Cerebrospinal fluid S-adenosylmethionine in depression and
dementia: effects of treatment with parenteral and oral S-adenosylmethionine. J Neurol Neurosurg
Psychiatr. 1990;53:1096-1098.
29. M.L. Hardy, I. Coulter, S.C. Morton, et al. S-Adenosyl-methionine (ademethionine) for treatment of
depression, osteoarthritis, and liver disease. Evid Rep Technol Assess (Summ). 2003;64:1-3.
30. G.M. Bressa. S-Adenosyl-l-methionine (SAMe) as antidepressant: meta-analysis of clinical studies. Acta
Neurol Scand. 1994;154(Suppl):7-14.
31. D. Mischoulon, M. Fava. Role of S-adenosyl-L-methionine in the treatment of depression: a review of the
evidence. Am J Clin Nutr. 2002;76(5 Suppl):1158s-1161s.
32. M. Spillman, M. Fava. S-Adenosyl-methionine (ademethionine) in psychiatric disorders. CNS Drugs.
33. R.D. Chiaie, P. Pancheri, S. Scapicchio. Efficacy and tolerability of oral and intramuscular
S-adenosyl-lmethionine 1,4-butanedisulfonate (SAMe) in the treatment of major depression: comparison with
imipramine in 2 multicenter studies. Am J Clin Nutr. 2002;76(Suppl):11172S-11176S.
34. J.E. Alpert, G. Papakostas, D. Mischoulon, et al. S-Adenosyl-L-methionine (SAMe) as an adjunct for
resistant major depressive disorder: an open trial following partial or nonresponse to selective serotonin
reuptake inhibitors or venlafaxine. J Clin Psychopharmacol. 2004;24(6):661-664.
35. E. Alvarez, C. Udina, R. Guillamat. Shortening of latency period in depressed patients treated with SAMe
and other antidepressant drugs. Cell Biol Rev. 1987;S1:103-110.
36. C. Berlanga, H.A. Ortega-Soto, M. Ontiveras, et al. Efficacy of S-adenosyl-L-methionine in speeding the
onset of action of imipramine. Psychiatry Res. 1992;44:257-262.
37. A. Barkai, D.L. Dunner, H.A. Gross, et al. Reduced myo-inositol levels in cerebrospinal fluid from
patients with affective disorder. Biol Psychiatry. 1978;13:65-72.
38. J. Levine, Y. Barak, M. Gonsalves, et al. Double-blind controlled trial of inositol treatment of depression.
Am J Psychiatry. 1995;152:792-794.