Thursday, May 20, 2010

SAMe (S-adenosyl-L-methionine)

SAMe is a substance naturally found in many of our body’s tissues and it is made up of the amino acid methionine (a sulfur containing amino acid) combined with adenosine. SAMe is used in a number of the body’s processes that require sulfur, especially the methylation reactions. There have been many favorable clinical studies on SAMe that indicate its potential as a therapy for osteoarthritis, depression and liver disease. SAMe’s general mechanism of action as a supplement is as a methyl donor for methylation reactions in our body’s natural processes. A deficiency of SAMe could be caused by a deficiency in the cofactors of its production, such as methionine, choline, and B vitamins. A defect in methylation may also cause a deficiency in SAMe. Overall, SAMe has been found to have anti-inflammatory, analgesic and anti-depressive effects.
One theory on depression and other neuropsychiatric disorders is that they are caused by a defect in our biochemical methylation process. Low levels of folate (used in methylation reactions) and serotonin have been linked to lower levels SAMe in depressed patients, and in clinical studies, the supplementation of SAMe has been shown to have an anti-depressant effect that also increases serotonin levels. The National Institute on Alcohol Abuse and Alcoholism and the Office of Dietary Supplements sponsored a conference examining the possible role of SAMe in treating alcoholic liver disease. Since oxidant stress is known to play a major role in the development of liver disease, and SAMe is involved in the manufacture of important liver antioxidant compounds (glutathione), it is being studied for its role in treatment of alcoholic liver disease. SAMe’s potential for osteoarthritis is based on its ability to support a higher production of proteoglycans, a substance that makes up cartilage.
SAMe seems to be a relatively safe and effective way of correcting our biochemical methylation process, what may be a route of cause for depression, osteoarthritis, liver disease, and other conditions. However, more clinical studies are needed for understanding exactly what kinds of depression SAMe works best for, more about its specific risks and therapeutic side effects, and its potential for other disease processes before it is an accepted treatment method for these and other conditions.
Scientific Support
A review of the published literature (from 1966 to 2001) on SAMe found that the majority of the clinical evidence for its use has been conducted on various depressive disorders, osteoarthritis, and fibromyalgia, and sample sizes and the dose used has varied widely. Several reviews and meta-analysis have been published all concluding that SAMe was better than placebo in treating depression, and equally as effective as the standard tricyclic antidepressants. However, the authors pointed out that even though SAMe seems well tolerated with most side effects being presented as gastrointestinal complaints, it may have the potential risk of psychiatric and cardiovascular adverse side effects. They concluded that until the side effects are more thoroughly researched, people should not be consuming it in an unmonitored fashion, and healthcare providers should be aware of the need for more research into the potential for adverse events (Fetrow and Avila, 2001; Bressa, 1994).
SAMe was tested in depressive patients and compared to imipramine in two multicenter studies. In one study (involving 143 patients over 6 weeks), 1600 mg of SAMe was given orally daily, and in the second study (involving 138 patients over 4 weeks) 400 mg of SAMe was given intramuscularly, and in both studies the SAMe treatment was compared (in 138 patients over 6 weeks) to the effects of 150 mg of imipramine given orally each day in a double-blind manner. The assessment measures were the Hamilton Depression Rating Scale (HAM-D) and the Clinical Global Impression at the endpoint. The authors stated that SAMe is the most important methyl donor in the central nervous system, and they concluded that both treatments of SAMe was as effective as 150 mg imipramine daily orally, but that SAMe was associated with significantly fewer adverse events (Delle Chiaie et al., 2002).
In one pilot study involving 13 depressed patients with Parkinson’s disease, for which no other previously tried antidepressant agents were effective (and were with intolerable side effects), SAMe was administered in doses of 800 to 3600 mg daily for 10 weeks. Ten of the eleven patients that completed the study showed at least a 50% improvement in the HAM-D score. One patient did not improve, and two dropped out due to increased anxiety. The only side effects noted in the others were mild nausea (in one patient) and mild and transient diarrhea (in two others). The authors concluded that this preliminary trial showed that SAMe is well tolerated and may be a safe alternative to current antidepressant agents used in Parkinson’s patients (DiRocco et al., 2000).
In an open, multi-center study involving 195 patients, 400 mg of SAMe was given parentally for 15 days. Depressive symptoms were found to decrease after days 7 and 15 of treatment with no serious adverse events reported. The authors concluded that further double-blind studies are need to confirm the findings that SAMe is not only a safe and effective anti-depressant, but that it is fast-acting, and could be a possible method for reducing the delay in antidepressant response (Fava et al., 1995).
The anti-depressive effect of SAMe was compared to desipramine in a double-blind randomized clinical study involving 26 patients. In the SAMe group, 62% showed significant improvement compared to 50% in the desipramine group. Regardless of the treatment group, the plasma SAMe concentration was shown to have been significantly improved in all patients that showed a 50% decrease in their HAM-D assessment. The authors concluded that this ladder finding showed that SAMe played a major role in regulating mood (Bell et al.,1994).
Another study examined the effect of SAMe in depressed postmenopausal women in a 30 day double-blind, placebo-controlled randomized design. Eighty women who were diagnosed with DSM-III-R major depressive disorder or dysthymia 6-36 months subsequent to menopause (either natural or through hysterectomy) were given 1,600 mg daily SAMe or placebo. A significant improvement was found in depressive symptoms compared to placebo starting day 10 of the study, and side effects were mild and transient (Salmaggi et al., 1993).
In an effort to study the effect of speeding up the onset of action of the antidepressant imipramine, SAMe was given to 40 patients in a double-blind manner alongside imipramine at 150 mg daily. The SAMe was administered at 200 mg daily intramuscularly. SAMe was concluded to effectively increase the onset of antidepressive action of imipramine (Berlanga et al., 1992).
In one earlier study, SAMe was administered both orally and intravenously and levels of SAMe were found to significantly rise in the cerebrospinal fluid, indicating that it crossed the blood-brain barrier. The authors also pointed out that SAMe levels were low in a group of Alzheimer’s patients, and that this suggested a problem in methylation in the disease that the possible use of SAMe as treatment (Bottiglieri et al., 1990).
A meta-analysis of randomized controlled clinical trials was conducted on the use of SAMe compared to nonsteroidal anti-inflammatory drugs (NSAIDs) for osteoarthritis. SAMe was found to be as effective as NSAIDs as reducing pain and functional limitation of osteoarthritis but without the side effects associated with NSAIDs (Soeken et al., 2002).
In another meta-analysis of the use of SAMe in osteoarthritis, all randomized clinical trials on SAMe and oxaceprol were reviewed for their efficacy in osteoarthritis. Assessments of clinical trials were based mostly on pain scores and pain and function scores. Because there were only a few trials that had a mixture of results, the authors cautioned that the results of the meta-analysis had to be interpreted very carefully, but that overall there was not enough evidence to recommend using SAMe and oxaceprol for the treatment of osteoarthritis, but that there was a comparable effect of them to NSAIDs (Witte et al., 2002).
SAMe was tested in a bicentric, randomized, double-blind, placebo-controlled study on its effectiveness for treatment on 81 patients with osteoarthritis. After a 7-day washout period, patients were administered either 400 mg boluses of SAMe i.v. for 5 days followed by 200 mg three times daily for 23 days or a matching placebo regimen. The major outcome measures were the Stanford Health Assessment Questionnaire disability and pain scales, and supplemental visual analog scales for rest and walking pain. In one center, where the patients tended to have a milder baseline of osteoarthritis, the SAMe showed a significantly greater effect in reducing overall pain and resting pain than placebo. In the other center, the baseline osteoarthritis was much more severe, and there was no difference between treatment groups in outcome measures. The authors concluded SAMe to be beneficial to the treatment of osteoarthritis in some patients, and that intravenous loading of SAMe may be an more effective strategy to beginning oral treatment (Bradley et al., 1994).
In one study of SAMe for fibromyalgia, 34 patients were given 600 mg i.v. or placebo for 10 days in a double blind cross-over trial. The primary outcome measure was the tender point change between the treatment groups, and there was no significant difference between the two found, even though there was a trend towards the SAMe group showing significantly improved measures of perception of pain (Volkmann et al., 1997).
In another study on fibromyalgia treatment using SAMe, 800 mg of SAMe was administered orally daily or placebo for 6 weeks in a double-blind, placebo controlled study. The outcome parameters measured that showed improvement vs. placebo were clinical disease activity, subjective symptoms (visual analog scale) of pain experienced during the last week, fatigue, and morning stiffness, and mood parameters evaluated by the Face Scale. Parameters for which there was no improvement found were tender point score, isokinetic muscle strength, and mood evaluated by Beck Depression Inventory. The authors noted that there were no differences in side effects between treatment and placebo groups, and concluded SAMe to be beneficial to primary fibromyalgia (Jacobsen et al., 1991).
Liver Disease
A review of clinical and preclinical science on SAMe was performed in order to give relevance to new findings of the role of SAMe in liver growth, differentiation and injury. Through genome sequence analysis, it was revealed that all organisms make SAMe, and a large percentage of all genes are SAMe dependent methyltransferases. Since most methylation reactions occur in the liver and a large percentage of methionine metabolism occurs in the liver, the authors contended that the liver is essential in the regulation of blood methionine. They added that SAMe is not only an intermediate in methionine catabolism, but that it is a control switch that works intracellularly to regulate liver regeneration, differentiation and protection (Mato et al., 2002).
A systematic review of the clinical studies on the use of SAMe in alcoholic liver disease was performed. Once the clinical studies were compiled, the methodology of each one was assessed using the components of quality and the Jadad-score. In the review, there were 8 placebo-controlled randomized clinical trials found, and of these, only one of them (involving 123 patients) used the adequate methodology and reported with clarity on mortality and liver transplantation. The authors found no significant effect of SAMe on mortality, liver related mortality, liver transplantation or liver complications, and therefore did not recommend it for alcoholic liver disease outside clinical trials (Rambaldi and Gluud, 2001; Mato et al. 1999).
SAMe was tested in a randomized placebo-controlled study involving 32 women with intrahepatic cholestasis of pregnancy. The study groups were divided into those who were treated with (a) ursodeoxycholic acid, (b) SAMe, (c) both drugs, or (d) a placebo. The authors found the combination treatment, group (c) to be significantly more effective than placebo or than either drug alone (groups a, b or d) (Nicastri et al., 1998).
In another study comparing SAMe treatment to ursodeoxycholic acid for intrahepatic cholestasis of pregnancy, 20 women were treated with either SAMe (1000 mg/day i.m.) or ursodeoxycholic acid (450 mg/day) from the last trimester of pregnancy until time of delivery. Ursodeoxycholic acid was shown to be more effective at treating pruritus and total bile acids than SAMe, and was recommended for further testing in this indication (Floreani et al., 1996). Earlier studies on the use of SAMe for intrahepatic cholestasis of pregnancy have likewise given mixed results (Ribalta et al., 1991; Frezza et al.,
Parkinson’s Disease
See DiRocco et al., 2000 in the section above on Depression.
Safety / Dosage
Experimental studies have found that SAMe does not cause the same side effects as other non-steroidal anti-inflammatory agents, such as aspirin, on the gastric irritation, or by interfering with blood clotting mechanisms, or inhibition of prostaglandins. In clinical studies the side effects noted have been mostly mild and transient, especially gastrointestinal discomfort.
SAMe appears to be well absorbed through intravenous and intramuscular routes, and through oral administration if an enteric-coated capsule is used. In clinical studies, the amounts taken ranged from 600 to 1,600 mg a day for osteoarthritis. For depression, higher amounts of SAMe are recommended, starting with a high dosage of 1,600 mg daily (divided into two or four doses per day) for two to three weeks, and then to reduce the dosage to a maintenance level depending on the individuals’ depressive symptoms (such as 800 mg or 400 mg daily). Preclinical studies suggest that SAMe functions when folate and vitamin B12 levels are normal (not low) (Grazi and Costa, 1999).
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3.Bottiglieri T, Godfrey P, Flynn T, Carney MW, Toone BK, Reynolds EH. Cerebrospinal fluid S-adenosylmethionine in depression and dementia: effects of treatment with parenteral and oral S-adenosylmethionine. J Neurol Neurosurg Psychiatry. 1990 Dec;53(12):1096-8.
4.Bradley JD, Flusser D, Katz BP, Schumacher HR Jr, Brandt KD, Chambers MA, Zonay LJ. A randomized, double blind, placebo controlled trial of intravenous loading with S-adenosylmethionine (SAM) followed by oral SAM therapy in patients with knee osteoarthritis. J Rheumatol. 1994 May;21(5):905-11.
5.Bressa GM. S-adenosyl-l-methionine (SAMe) as antidepressant: meta-analysis of clinical studies. Acta Neurol Scand Suppl. 1994;154:7-14.
6.Delle Chiaie R, Pancheri P, Scapicchio P. Efficacy and tolerability of oral and intramuscular S-adenosyl-L-methionine 1,4-butanedisulfonate (SAMe) in the treatment of major depression: comparison with imipramine in 2 multicenter studies. Am J Clin Nutr. 2002 Nov;76(5):1172S-6S.
7.Di Rocco A, Rogers JD, Brown R, Werner P, Bottiglieri T. S-Adenosyl-Methionine improves depression in patients with Parkinson's disease in an open-label clinical trial. Mov Disord. 2000 Nov;15(6):1225-9.
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12.Grazi, S. and Costa, M. The European Arthritis and Depression Breakthrough: SAMe. 1999. Prima Health: Rocklin, CA. 248 pp.
13.Mato JM, Camara J, Fernandez de Paz J, Caballeria L, Coll S, Caballero A, Garcia-Buey L, Beltran J, Benita V, Caballeria J, Sola R, Moreno-Otero R, Barrao F, Martin-Duce A, Correa JA, Pares A, Barrao E, Garcia-Magaz I, Puerta JL, Moreno J, Boissard G, Ortiz P, Rodes J. S-adenosylmethionine in alcoholic liver cirrhosis: a randomized, placebo-controlled, double-blind, multicenter clinical trial J Hepatol. 1999 Jun;30(6):1081-9.
14.Mato JM, Corrales FJ, Lu SC, Avila MA. S-Adenosylmethionine: a control switch that regulates liver function. FASEB J. 2002 Jan;16(1):15-26.
15.Nicastri PL, Diaferia A, Tartagni M, Loizzi P, Fanelli M. A randomised placebo-controlled trial of ursodeoxycholic acid and S-adenosylmethionine in the treatment of intrahepatic cholestasis of pregnancy. Br J Obstet Gynaecol. 1998 Nov;105(11):1205-7.
16.Rambaldi A, Gluud C. S-adenosyl-L-methionine for alcoholic liver diseases. Cochrane Database Syst Rev. 2001;(4):CD002235.
17.Ribalta J, Reyes H, Gonzalez MC, Iglesias J, Arrese M, Poniachik J, Molina C, Segovia N. S-adenosyl-L-methionine in the treatment of patients with intrahepatic cholestasis of pregnancy: a randomized, double-blind, placebo-controlled study with negative results. Hepatology. 1991 Jun;13(6):1084-9.
18.Salmaggi P, Bressa GM, Nicchia G, Coniglio M, La Greca P, Le Grazie C. Double-blind, placebo-controlled study of S-adenosyl-L-methionine in depressed postmenopausal women. Psychother Psychosom. 1993;59(1):34-40.
19.Soeken KL, Lee WL, Bausell RB, Agelli M, Berman BM. Safety and efficacy of S-adenosylmethionine (SAMe) for osteoarthritis. J Fam Pract. 2002 May;51(5):425-30.
20.Volkmann H, Norregaard J, Jacobsen S, Danneskiold-Samsoe B, Knoke G, Nehrdich D. Double-blind, placebo-controlled cross-over study of intravenous S-adenosyl-L-methionine in patients with fibromyalgia. Scand J Rheumatol. 1997;26(3):206-11.
21.Witte S, Lasek R, Victor N. Meta-analysis of the efficacy of adenosylmethionine and oxaceprol in the treatment of osteoarthritis. Orthopade. 2002 Nov;31(11):1058-65.
EDITOR'S NOTE: This monograph can be found in The Health Professional's Guide to Dietary Supplements (Lippincott, Williams & Wilkins) by Shawn M. Talbott, PhD and Kerry Hughes, MS.

St. John's Wort

St. John’s wort (Hypericum perforatum), also called Klamath weed, is a five-petaled yellow flower, which is especially plentiful in Northern California and Southern Oregon. The “St. John’s” name comes from the red color of the extract (from squeezed buds and flowers), which was associated with the blood of St. John the Baptist and the fact that the herb typically flowers around the time of the feast of St. John. St. John’s wort has been used for centuries for everything from a “protector against evil spirits” (depression) and for wound healing to its most common present-day use as an antidepressant. The active ingredients in St. John’s wort extract are unknown, but extracts standardized to contain napthodianthrone compounds such as hypericin and pseudohypericin along with phloroglucinols such as hyperforin and adhyperforin are known to be effective in alleviating mild to moderate depressive symptoms.
As an antidepressant, St. John’s wort has been shown to inhibit an enzyme (catechol-O-methyltransferase) which degrades certain neurotransmitters such as dopamine. It has also been shown to inhibit serotonin re-uptake in the brain, and to reduce expression of interleukin-6 and gamma-amino butyric acid (GABA) uptake. Each of these actions can contribute to alleviating depression by slowing the recycling of neurotransmitters needed for maintaining emotional balance. As an anti-viral agent, St. John’s wort has been reputed to inhibit replication of several viruses, including the Herpes simplex, HIV, and the virus that causes mononucleosis, but its use as a dietary supplement for treating viral infections is generally not supported.
St. John's wort appears to be helpful in about 50-60% of cases of mild to moderate depression – but as with prescription antidepressants, the full effect takes about 4-6 weeks to develop. It is important to note that St. John's wort should never be used for the treatment of severe depression (feelings of suicide, extreme inability to cope with daily life, severe anxiety, or extreme fatigue) – and physician-directed drug therapy may mean the difference between life and death.
That said, St. John’s wort is sold in a variety of forms, including tea, drops, tablets, and capsules. In tablet or capsule form, standardized St. John’s wort extracts, (300-900mg/day) represent a relatively safe and effective dietary supplement for those with mild to moderate depression, anxiety, or seasonal affective disorder.
Scientific Support
Several clinical studies have been conducted to determine the efficacy of St. John’s wort for those with mild to moderate depression. In one review of 23 randomized trials (15 placebo-controlled and 8 drug comparisons) including nearly 2,000 patients with mild or moderate depressive disorders, extracts of St. John’s wort were nearly 3 times more effective than placebo, and were comparable to prescription anti-depressants and with fewer side effects (Gaster & Holroyd 2000). Across the studies, fewer than 1% of those taking St. John’s wort dropped out of the study, compared with a drop-out rate of 3% taking a prescription anti-depressant. Perhaps the most encouraging results were that in contrast to the high percentage of side effects in those taking prescription anti-depressants (52.8%), only 19.8% of those taking St. John’s wort experienced any adverse effects (Linde et al. 1996). Other well-controlled studies comparing the St. John’s wort extract LI 160 (from Lichtwer Pharma) to prescription anti-depressants such as Prozac (fluoxetine), sertraline (Zoloft), paroxetine (Paxil), imipramine, amitriptyline and maprotiline have all found St. John’s wort to be comparable in effectiveness, but superior to prescription drugs with regard to tolerability. Overall, more than a dozen double-blind placebo-controlled studies have been conducted (mostly small studies) with the majority supporting the case for the effectiveness of St. John's wort in alleviating mild to moderate depression (Hansgen et al. 1994; Harrer et al. 1994; Philipp et al. 1999.
In the one recent study in the literature that explored the use of St. John’s wort as a retroviral agent for use in HIV-infected patients (Woelk et al. 1994), over half of the patients discontinued treatment early because of severe cutaneous phototoxicity (skin sensitivity to sunlight exposure). Of those who remained in the study, there were no significant changes in virologic markers. It should be noted that HIV-positive patients should NOT use St. John’s wort without specific advise and consultation of their personal physician, as the herb has been shown to almost completely inactivate the effects of certain antiviral medications (indinavir and other protease inhibitors).
St. John’s wort is quite safe in terms of observed side effects, the most common of which are typically mild gastrointestinal upset, mild allergic reactions (skin rash), tiredness and insomnia/restlessness. There have been no published reports of serious adverse side effects from taking the herb alone and animal studies with large doses of St. John’s wort have not shown any serious problems. The most commonly studied adverse effect of St. John’s wort is its ability to cause photosensitivity, especially in fair-skinned individuals. This condition is reversible upon discontinuation of the herb. Thus, special care should be taken to avoid ultraviolet light, or to frequently apply sunscreen and wear sunglasses (due to an increased risk of cataracts) when it is necessary to be outside. Other side effects include gastrointestinal symptoms, dizziness, confusion and tiredness, and tend to be equivalent in incidence to placebo.
Scientific studies conducted in vitro (test tube studies) have shown St. John’s wort to be mutagenic and toxic to sperm, suggesting that it should not be taken when trying to become pregnant. On the other hand, St. John’s wort has also been shown to interfere with the action of certain oral contraceptives (birth control pills). St. John’s wort is not recommended for children, or for women who are pregnant or lactating.
Although direct side effects from consuming St. John’s wort appear to be quite rare, several recent reports have raised the possibility that the herb may interact with and decrease the effectiveness of various medications, including HIV drugs (protease inhibitors), immunosuppressants (such as cyclosporin for organ transplants), digoxin (for congestive heart failure), blood thinners (Coumadin/warfarin), chemotherapy drugs, (olanzapine/clozapine) and asthma medications (theophylline). If you are currently taking any of these, or other prescription medications, DO NOT begin taking OR discontinue taking St. John’s wort without first consulting your personal physician (abrupt withdrawal of the herb could increase blood levels of various medications, which could be dangerous in certain cases).
The recommended dosage for St. John’s wort is 900mg per day (300mg taken 3 times per day) of an extract of the flowers and leaves standardized to contain 0.3% hypericin in a complex of other natural compounds, or 3-5% hyperforin (the main constituent which is thought to inhibit neurotransmitter re-uptake). Minimal treatment time is 4-6 weeks. St. John’s wort is sold in the U.S. only as an herbal supplement, although it is marketed as a drug in Germany for the treatment of mild depression and anxiety.
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EDITOR'S NOTE: This monograph can be found in The Health Professional's Guide to Dietary Supplements (Lippincott, Williams & Wilkins) by Shawn M. Talbott, PhD and Kerry Hughes, MS.


Valerian (Valeriana officinalis or Valerianae radix) has been used as a medicinal anti-anxiety herb and sleep aid since the days of the Romans. The dried roots of the plant are used in teas, tinctures and in capsule/tablet forms. The fresh root has no distinctive odor, however, over time hydrolysis of compounds present in the volatile oil produce isovaleric acid, which has an offensive odor (akin to sweaty socks). Traditionally valerian was used to treat migraine headache, anxiety, fatigue, and seizures and many traditional Chinese remedies include valerian for treatment of numbness due to rheumatic conditions, colds, menstrual difficulties, bruises and wound healing. Currently, valerian may be used orally for the treatment of insomnia, restlessness, sleeping disorders with anxiety, mood disorders, muscle and joint pain, menstrual cramps and menopausal symptoms. It is unclear which of the numerous compounds is the true “active” – but the combination of compounds appears to work together in the brain to produce an overall effect similar to the action of prescription tranquilizers such as Valium and Halcion.
As a mild tranquilizer and sleep aid, valerian may be an effective herb for dealing with temporary feelings of anxiety, nervousness or insomnia. The effects of valerian are generally quite mild when compared to prescription products and synthetic OTC products and generally do not result in “morning after hangover” effects experienced with certain sleep aids.
Scientific Support
Valerian taken before bedtime appears to reduce the amount of time that it takes to fall asleep (sleep latency). It is unknown, however, whether the quality of the sleep is affected by valerian consumption. Valerian is generally regarded as a mild tranquilizer and has been deemed safe by the German Commission E for treating “restlessness and sleeping disorders brought on by nervous conditions” (Donath et al. 2000). The medicinal portion of the valerian plant is the root and most of the pharmacological effects of valerian root have been attributed to valepotriate and volatile oil constituents, specifically monoterpenes and sesquiterpenes. However, it is hypothesized that multiple constituents are responsible for its therapeutic effects rather than to a single active compound. Valepotriate constituents are believed to have sedative-hypnotic and spasmolytic effects, while the sesquiterpenes, valerenic acid and kessyl glycol have been shown to cause sedation in animals (Houghton 1999). Another mechanism of action is likely to involve valerenic acid’s ability to inhibit the enzyme system responsible for the central catabolism of GABA, increasing GABA concentrations and decreasing CNS activity (Houghton 1999).
Several studies have examined the effects of valerian on sleep. In one placebo-controlled crossover study with 128 participants, 400mg of valerian extract (plus hops) reduced sleep latency and improved sleep quality compared with placebo (Leathwood et al. 1982). Analysis of the results suggested that valerian had an increased effect with participants that described themselves as “poor” or “irregular” sleepers. Another trial evaluated the effectiveness of 450-900mg of valerian on healthy volunteers between the ages of 21 and 44 (Kuhlmann et al. 1999). Sleep quality was measured using a questionnaire, night-time motor activity recordings, and spectral analysis of the sleep EEG. Both doses elicited mild hypnotic effects and improved sleep quality. Other studies of valerian supplementation have shown improvements in slow-wave (deeper stage) sleep, compared with placebo and equivalence of 600mg valerian with 10mg oxazepam for indices of overall sleep quality (Vonderheid-Guth et al. 2000). In terms of anxiolytic effects, several studies have shown 100-300mg of valerian root extract to be more effective than placebo and as effective as 20mg propranolol on measures of social stress, somatic arousal, anxiety, and emotional tension (Kuhnen & Oswald 1988).
Occasional reports of headaches and mild nausea are documented, but habituation or dependency is unlikely when used as directed. Valerian should be avoided by pregnant and lactating women and should not be consumed by children. Individuals currently taking sedative drugs or antidepressant medications should be advised by their personal physician before taking valerian. Do not take valerian in conjunction with alcohol or other tranquilizers and do not consume for more than two weeks.
Because the activity and strength of valerian preparations can vary significantly from one product to the next, it is recommended to select a standardized product (0.5-1.0% valerenic acids) whenever possible and to follow the directions on the particular product. As a general guideline, approximately 200-900mg of a standardized extract can be taken 30-60 minutes before bed (as a sleep aid) or as needed as a mild tranquilizer.
1.Assemi, Mitra Pharm D. Herbs Affecting the Central Nervous System: Gingko, Kava, St. John’s Wort, and Valerian. Clinical Obstetrics and Gynecology 2001; 44(4): 824-835.
2.Balderer G, Borbely AA. Effect of valerian on human sleep. Psychopharmacology (Berl). 1985;87(4):406-9.
3.Cauffield JS, Forbes HJ. Dietary supplements used in the treatment of depression, anxiety, and sleep disorders. Lippincotts Prim Care Pract. 1999 May-Jun;3(3):290-304.
4.Donath F, Quispe S, Diefenbach K, Maurer A, Fietze I, Roots I. Critical evaluation of the effect of valerian extract on sleep structure and sleep quality. Pharmacopsychiatry. 2000 Mar;33(2):47-53.
5.Heiligenstein E, Guenther G. Over-the-counter psychotropics: a review of melatonin, St John's wort, valerian, and kava-kava. J Am Coll Health. 1998 May;46(6):271-6.
6.Houghton PJ. The scientific basis for the reputed activity of Valerian. J Pharm Pharmacol. 1999 May;51(5):505-12.
7.Kammerer E. Phytogenic sedatives-hypnotics--does a combination of valerian and hops have a value in the modern drug repertoire? Z Arztl Fortbild (Jena). 1993 Apr 12;87(5):401-6.
8.Kirkwood CK. Management of insomnia. J Am Pharm Assoc (Wash). 1999 Sep-Oct;39(5):688-96.
9.Kohnen R, Oswald WD. The effects of valerian, propranolol, and their combination on activation, performance, and mood of healthy volunteers under social stress conditions. Pharmacopsychiatry. 1988 Nov;21(6):447-8.
10.Kuhlmann J, Berger W, Podzuweit H, Schmidt U. The influence of valerian treatment on "reaction time, alertness and concentration" in volunteers. Pharmacopsychiatry. 1999 Nov;32(6):235-41.
11.Leathwood PD, Chauffard F, Heck E, Munoz-Box R. Aqueous extract of valerian root (Valeriana officinalis L.) improves sleep quality in man. Pharmacol Biochem Behav. 1982 Jul;17(1):65-71.
12.Leathwood PD, Chauffard F. Aqueous extract of valerian reduces latency to fall asleep in man. Planta Med. 1985 Apr;(2):144-8.
13.Plushner SL. Valerian: Valeriana officinalis. Am J Health Syst Pharm. 2000 Feb 15;57(4):328, 333, 335.
14.Schulz H, Stolz C, Muller J. The effect of valerian extract on sleep polygraphy in poor sleepers: a pilot study. Pharmacopsychiatry. 1994 Jul;27(4):147-51.
15.Vonderheid-Guth B, Todorova A, Brattstrom A, Dimpfel W. Pharmacodynamic effects of valerian and hops extract combination (Ze 91019) on the quantitative-topographical EEG in healthy volunteers. Eur J Med Res. 2000 Apr 19;5(4):139-44.
16.Willey LB, Mady SP, Cobaugh DJ, Wax PM. Valerian overdose: a case report. Vet Hum Toxicol. 1995 Aug;37(4):364-5.
17.Wong AH, Smith M, Boon HS. Herbal remedies in psychiatric practice. Arch Gen Psychiatry. 1998 Nov;55(11):1033-44.
EDITOR'S NOTE: This monograph can be found in The Health Professional's Guide to Dietary Supplements (Lippincott, Williams & Wilkins) by Shawn M. Talbott, PhD and Kerry Hughes, MS.


Vinpocetine is a derivative of the alkaloid (extracted from Vinca minor) vincamine, and is used in many countries in the treatment and prevention of stroke and vascular dementia. Although there has not been one single mechanism of action agreed upon for vinpocetine, there are many known activities that contribute to its use such as dilating blood vessels, enhancing circulation to the brain, improving oxygen utilization and reducing blood clotting, and inhibition of platelet aggregation. Vinpocetine works on altering the ischemic cascade in several different areas, including ATP depletion, activation of voltage-sensitive sodium and calcium channels, glutamate and free radicals release. The most important of these effects to its neuroprotective activity seems to be the interference of voltage-sensitive sodium channels, and possibly also its strong antioxidant activity (Hadjiev, 2003).
One main Hungarian company markets vinpocetine in Europe as a drug (Cavinton) for improving several types of cerebral insufficiency conditions, and for improving cerebral metabolism. In studies involving vinpocetine’s use in chronic stroke patients, positron emission tomography (PET) scans showed that it improves the brain metabolism and blood flow, especially around the stroke-damaged areas (Szakal et al., 1998; Vas et al., 2002; Gulyas et al., 2002).
There seems to be a good amount of preclinical science and little clincial science to back vinpocetine’s use in cerebrovascular disorders. However, with its low toxicity and side effects, it shows excellent potential for the future use of prevention and treatment of stroke. Its effects on memory on healthy individuals has some merit, but yet needs more clinical backing.
Scientific Support
Cerebrovascular Disease
Hadjiev (2003) reviewed the actions of vinpocetine on the ischemic cascade, and discussed how it may be a new therapeutic approach to treatment and prophylactic neuroprevention in patients with asymtomatic ischemic cerebrovascular disorders (AICVD) and cerebrovascular disease. A subclinical noninvasive diagnosis of AICVD has been recently introduced by the American Heart Association and its treatment was identified as being important in prevention of ischemic stroke and cognitive decline. As a potential treatment to AICVD, the neuroprotective effects of vinpocetine were discussed.
Szapary et al. (2003) examined the high and low dose therapy of vinpocetine on rheological parameters in acute and chronic stroke patients. Vinpocetine is used mainly in a preventative manner, and this study sought to determine if it had value as a treatment for chronic disease. The authors concluded that after parenteral administration with low (30 mg/day) and high (70 mg/day) doses of vinpocetine, the high dose showed significant decreases in hematocrit, the whole blood and plasma viscosity and red blood cell aggregation, indicating a beneficial role in the treatment of chronic cerebrovascular disease.
A pilot clinical study involving the treatment of 30 patients with vinpocetine was conducted in order to determine the safety and feasibility of a full-scale clinical study. Patients were given either dextran alone or dextran in combination with vinpocetine and it was found that the two treatment groups were comparable in their major prognostic variables. However, the National Institute of Health Stroke Scale score was slightly improved in the vinpocetine group at 3 months of follow-up, and no significant side effects were seen. A full-scale clinical study was concluded to be warranted (Feigin et al., 2001).
A systematic review of the literature and researchers in the field (including drug companies) was conducted to determine if therapy with vinpocetine on stroke was effective. Only one trial was found that was of an unconfounded randomized, placebo controlled design. The authors concluded that there were no deaths found, nor drug dependencies, but that there were not enough studies conducted to determine the efficacy of vinpocetine in stroke patients (Bereczki and Fekete, 2000; Bereczki and Fekete, 1999).
As vinpocetine had been used for over 20 years in the treatment of cognitive impairment due to vascular diseases, and there had been many preclinical findings to suggest several important mechanisms of action, no consensus had been reached on its efficacy. Therefore this search was conducted to review the existing literature world-wide to analyze unconfounded double-blind studies pertaining to vinpocetine treatment of vascular dementia, Alzheimer’s dementia and other dementias. The authors concluded that although the preclinical science done on vinpocetine was persuasive and few adverse effects were found, the clinical science was inconclusive and did not support clinical use. The authors called for more clinical work on well-defined types of cognitive impairment. (Szatmari and Whitehouse, 2003).
Twelve healthy females were given vinpocetine in the dosages of 10, 20, or 40 mg for two days or placebo and assessed for psychopharmacological effects in a randomized, double-blind crossover study. Assessment parameters were measured on the third day, and included Critical Flicker Fusion (CFF), Choice Reaction Time (CRT), Subjective Ratings of Drug Effects (LARS), and Sternberg Memory Scanning Test. Significant improvements were found in memory as a function of the Sternberg test at the dosage level of 40 mg. The results suggested that vinpocetine has a specific effect on the serial comparison stage of the reaction process (Subhan and Hindmarch, 1985).
Safety / Dosage
For the use of improving mild to moderate dementia in patients, 5-10 mg, taken 2-3 times daily, is the typical dosage recommendation, however larger dosages have been used clinically for acute treatment. Because vinpocetine is difficult to absorb in large quantities, it is recommended to divide the daily doses as suggested.
Side effects of vinpocetine are rare and transient (with discontinued use) at the recommended dosages. Typically these side effects may include gastrointestinal upset, low blood pressure, dry mouth, insomnia, headaches and heart palpitations. Persons on anti-coagulant therapy should not use vinpocetine, as it may interfere with clotting.
The safety or efficacy of vinpocetine for pregnant or lactating women is undocumented.
1.Bereczki D, Fekete I. Vinpocetine for acute ischaemic stroke. Cochrane Database Syst Rev. 2000;(2):CD000480.
2.Bereczki D, Fekete I. A systematic review of vinpocetine therapy in acute ischaemic stroke. Eur J Clin Pharmacol. 1999 Jul;55(5):349-52.
3.Feigin VL, Doronin BM, Popova TF, Gribatcheva EV, Tchervov DV. Vinpocetine treatment in acute ischaemic stroke: a pilot single-blind randomized clinical trial. Eur J Neurol. 2001 Jan;8(1):81-5.
4.Gulyas B, Halldin C, Sandell J, Karlsson P, Sovago J, Karpati E, Kiss B, Vas A, Cselenyi Z, Farde L. PET studies on the brain uptake and regional distribution of [11C]vinpocetine in human subjects. Acta Neurol Scand. 2002 Dec;106(6):325-32.
5.Hadjiev D. Asymptomatic ischemic cerebrovascular disorders and neuroprotection with vinpocetine. Ideggyogy Sz. 2003 May 20;56(5-6):166-72
6.Subhan Z, Hindmarch I. Psychopharmacological effects of vinpocetine in normal healthy volunteers. Eur J Clin Pharmacol. 1985;28(5):567-71.
7.Szapary L, Horvath B, Alexy T, Marton Z, Kesmarky G, Szots M, Nagy F, Czopf J, Toth K. [Effect of vinpocetin on the hemorheologic parameters in patients with chronic cerebrovascular disease] Orv Hetil. 2003 May 18;144(20):973-8.
8.Szakall S, Boros I, Balkay L, Emri M, Fekete I, Kerenyi L, Lehel S, Marian T, Molnar T, Varga J, Galuska L, Tron L, Bereczki D, Csiba L, Gulyas B. Cerebral effects of a single dose of intravenous vinpocetine in chronic stroke patients: a PET study. J Neuroimaging. 1998 Oct;8(4):197-204.
9.Szatmari SZ, Whitehouse PJ. Vinpocetine for cognitive impairment and dementia. Cochrane Database Syst Rev. 2003;(1):CD003119.
10.Vas A, Sovago J, Halldin C, Sandell J, Karlsson P, Karpati E, Kiss B, Cselenyi Z, Farde L, Gulyas B. Cerebral uptake and regional distribution of [11C]-vinpocetin after intravenous administration to healthy men: a PET study. Orv Hetil. 2002 Nov 24;143(47):2631-6.
EDITOR'S NOTE: This monograph can be found in The Health Professional's Guide to Dietary Supplements (Lippincott, Williams & Wilkins) by Shawn M. Talbott, PhD and Kerry Hughes, MS.


As alfalfa has long been a fodder plant used for livestock and horses, much of what has been studied in the scientific literature is based on its use in animals. It has been revered as a food for horses that gives increases strength and speed, and this has contributed to its folkloric use as an herbal supplement for increasing energy, lowering cholesterol, detoxification, arthritis and hot flashes associated with menopause.
Alfalfa truly is a nutritive food, with high levels of protein (up to 50%), B-vitamins, and minerals, and this could go a long way in explaining its claims for energy and reduction of fatigue. Additionally, alfalfa contains saponins which could explain some of its “adaptogenic” reputation, and antioxidants and its alkalizing nature could explain its detoxification claims. Its use in hot flashes and cancer may be explained by its high estrogenic activity.
Alfalfa is still lacking in clinical research to back up its many claims, but as a nutritive food it may add credence to its use in many kinds of wellness formulations. In a recent study on the estrogenic activity of several legumes, alfalfa sprout extract was found to increase cell proliferation above levels found for estradiol, and the authors concluded it to contain phytoestrogens with a high level of activity (Boue et al., 2003).
Scientific Support
Supplementation of alfalfa seeds was clinically tested in patients with hyperlipoproteinemia (HLP) types IIA, IIB, and IV. All patients were given 40 g of alfalfa seeds 3 times daily with meals for 8 weeks. At the end of the 8 week period, there was a 17% lowering of total plasma cholesterol, and an 18% decrease in the low density lipoprotein (LDL) levels in patients with type II HLP. The largest decreases observed were 26% in total cholesterol and 30% in LDL. The authors concluded that the alfalfa seeds may be used to normalize serum cholesterol levels in patients with type II HLP (Molgaard et al., 1987).
Safety / Dosage
Although the dosage used in the clinical study on alfalfa’s use for lowering cholesterol was extremely high (120 grams daily!), typical dosages for alfalfa tend to range from 250-1000 mg 2-3 times daily with meals. In this dosage range, there are no known side effects of alfalfa except a possible mild blood thinning effect.
1.Boue SM, Wiese TE, Nehls S, Burow ME, Elliott S, Carter-Wientjes CH, Shih BY, McLachlan JA, Cleveland TE. Evaluation of the estrogenic effects of legume extracts containing phytoestrogens. J Agric Food Chem. 2003 Apr 9;51(8):2193-9.
2.Molgaard J, von Schenck H, Olsson AG. Alfalfa seeds lower low density lipoprotein cholesterol and apolipoprotein B concentrations in patients with type II hyperlipoproteinemia. Atherosclerosis. 1987 May;65(1-2):173-9.
EDITOR'S NOTE: This monograph can be found in The Health Professional's Guide to Dietary Supplements (Lippincott, Williams & Wilkins) by Shawn M. Talbott, PhD and Kerry Hughes, MS.


L-Arginine is a substance that is produced in the body that plays an essential role in the nitric oxide pathway, a pathway involved in the cascade reactions that are responsible for vasodilation. Due to this function, arginine supplements are associated with cardiovascular health, especially in conditions where the nitric oxide pathway may be working insufficiently. For example, there is evidence that in the development of arteriosclerosis, people with high cholesterol have an endothelium that has the reduced ability to produce nitric oxide, and therefore the arteries can not dilate effectively. This leads to the consequence of blood cells having the ability to attach to the inner vessels and cause blockages. L-Arginine has also been shown to stimulate lymphocyte production, and it has therefore been studied in diets of surgery patients.
During the nitric oxide pathway, the nitric oxide synthase enzyme catalyzes the oxidation of arginine to citrulline and nitric oxide (NO). NO production in turn causes vasodilation, and is involved in the overall regulation of overall vasoresistance. Since arginine is produced by our bodies it has been classified as a nonessential nutrient for supplementation, however, recently the amount of arginine produced by the body has been found to be insufficient for maintaining health.
Due to the popularity of dietary supplements for sexual function improvement and the known action of arginine on the NO pathway, numerous supplements now include arginine in combination with other herbs for sexual dysfunction and performance. However, few studies have confirmed the benefits of these combinations nor the action of the single components.
Scientific Support
Cardiovascular Health
A meta-analysis of the use of L-arginine in the enteral/oral diets of stressed patients was conducted to reduce the confusion of whether or not the diets were immune enhancing and beneficial. Although the review found these L-arginine “immune-enhancing” diets to be beneficial, the author contended that nothing proved that this effect was not confounded by other bioactive components, including omega-3 fatty acids, RNAs, and antioxidant vitamins. The author also pointed out that the L-arginine supplemented enteral/oral diets could have a harmful effect in hemodynamically unstable patients, and in patients with multiple organ failure (Cynober, 2003).
A medical food called the Heart Bar is now sold that looks just like the numerous other sports and protein bars. The heart bar is intended to act as a food that nutritionally supports cardiovascular health with its major active constituent being arginine. Its use is substantiated by numerous peer reviewed clinical studies, and it is regulated specially as a “medical food” by the FDA. In one study (a randomized, double-blind, placebo-controlled, crossover trial), thirty-six stable angina outpatients were tested for the electrocardiographic, vascular and clinical effects of the Heart Bar. This medical food was found to improve vascular function, exercise capacity and aspects of quality of life in patients with stable angine (Maxwell et al., 2002).
L-Arginine was clinically studied in a single-blind, controlled, crossover dietary intervention study for its effect on certain cardiovascular parameters, especially blood pressure. Six subjects were given isocaloric diets for one week, with constant measures of sodium in each diet (approx. 180 mmol/day). Three diets were given in random order to each participant: a) control, b) L-arginine enriched by natural foods, and c) L-arginine supplemented orally (same as control diet otherwise). Both arginine-rich diets (b and c) resulted in a blood pressure decrease. The diet b ( but not diet c) resulted in lower total serum cholesterol and triglyceride levels and higher HDL cholesterol. The diet c, and to a lesser extent diet b, resulted in higher creatine clearance (slight) and a fall in fasting glucose. The authors concluded an increase of L-arginine in the diet to lower blood pressure and affect kidney function and carbohydrate metabolism (Siani et al, 2000).
Fujita et al. (2000) clinically tested the ability of L-arginine to affect coronary perfusion abnormality during exercise. Twelve patients with angina pectoris and normal coronary arteries underwent exercise thallium-201 scintigraphy both with intravenous L-arginine or without (control). The administration of L-arginine was found to prolong exercise time and improve the severity score. In 7 of the 12 patients, the TI-201 redistribution disappeared after L-arginine administration, and the percentage of serum L-citrulline increased, and percentage of epicardial coronary diameter in response to acetylcholine compared to the other patients who did not show a change in TI-201 redistribution. The authors concluded that exogenous L-arginine was able to improve myocardial perfusion during exercise in this subset of patients.
High Blood Pressure
In order to determine whether or not a deficient L-arginine-nitric oxide system is active in cortisol-induced hypertension, the effect of L-arginine uptake was studied. Eight healty men were included in the study, and hydrocortisone acetate (50 mg) was given orally every six hours for 24 hous after a 5-day fixed salt diet. L-Arginine levels were not found to be affected by cortisol treatment, and therefore, there was no correlation between cortisol induced hypertension and the L-arginine transport system (Chin-Dusting et al., 2003).
Immune Function
L-Arginine was clinically tested in patients with far advanced gastric cancer for its ability to stimulate lymphocyte production, since it had been previously shown to stimulate lymphocyte production in healthy individuals. The patients received a dietary supplement of L-arginine (30 g daily for 7 days), and the lymphocyte counts and T/B cell ratio in the peripheral blood was tested. Although L-arginine did not show any significant side effects (except transient nausea in 1 patient) or impair liver function, it also did not stimulate lymphocyte function. The authors suggested the possibility that the cancer patients had immune systems that were intrinsically defected, and therefore could not be stimulated (Wu et al., 1993).
Li et al. (1993) tested the ability of L-arginine to decrease incidence of sepsis after surgery in patients with obstructive jauntice. Since arginine had been known as a T lymphocyte stimulator, the use of supplementation and the immunological status of patients with obstructive jauntice after surgery was studied. Arginine was found to significantly enhance immune function of patients with obstructive jauntice.
In order to study the immunomodulatory effect of arginine in surgery patients, 30 cancer patients were randomized, and sixteen were given L-arginine (25 g/day) while the other 14 were given isonitrogenous L-glycine (43 g/day) for 7 days after major surgery. Parameters measured were nitrogen balance (daily), and immune parameters before and after surgery on days 1,4 and 7. T-Lymphocyte response was significantly enhanced to concanavalin A in the L-arginine group compared to the glycine group. L-arginine was also found to increase the CD4 phenotype. L-Arginine was found to be beneficial in modulating the immune system in surgery patients. This immune modulating effect was found to be nontoxic and distinct in its mechanism from its moderate effect on nitrogen metabolism (Daly et al., 1988).
Safety / Dosage
The daily requirement of arginine supplementation has been calculated to be approximately 8 grams daily (for a 70-kg person). Supplements in the range of 8-21 grams daily have been used clinically in people with high cholesterol in order to restore the proper functioning of the vasodilatory pathways. Supplements in the range of 9-14 grams daily have been used clinically to increase blood flow to the peripheries and improve conditions of myocardial ischemia and walking pain due to claudication.
The average daily intake of arginine in the American diet has been calculated to be approximately 5 grams daily. In order to increase arginine in the diet, the primary dietary sources of this amino acid are meats and other high protein foods (nuts, eggs).
1.Chin-Dusting JP, Ahlers BA, Kaye DM, Kelly JJ, Whitworth JA. L-arginine transport in humans with cortisol-induced hypertension. Hypertension. 2003 Jun;41(6):1336-40. Epub 2003 Apr 21.
2.Cynober L. Immune-enhancing diets for stressed patients with a special emphasis on arginine content: analysis of the analysis. Curr Opin Clin Nutr Metab Care. 2003 Mar;6(2):189-93.
3.Daly JM, Reynolds J, Thom A, Kinsley L, Dietrick-Gallagher M, Shou J, Ruggieri B. Immune and metabolic effects of arginine in the surgical patient. Ann Surg. 1988 Oct;208(4):512-23.
4.Fujita H, Yamabe H, Yokoyama M. Effect of L-arginine administration on myocardial thallium-201 perfusion during exercise in patients with angina pectoris and normal coronary angiograms. J Nucl Cardiol. 2000 Mar-Apr;7(2):97-102.
5.Li H, Xiong ST, Zhang SX, Liu SB, Luo Y. Immunological status of patients with obstructive jaundice and immunostimulatory effect of arginine. J Tongji Med Univ. 1993;13(2):111-5.
6.Maxwell AJ, Zapien MP, Pearce GL, MacCallum G, Stone PH. Randomized trial of a medical food for the dietary management of chronic, stable angina. J Am Coll Cardiol. 2002 Jan 2;39(1):37-45.
7.Siani A, Pagano E, Iacone R, Iacoviello L, Scopacasa F, Strazzullo P.Blood pressure and metabolic changes during dietary L-arginine supplementation in humans. Am J Hypertens. 2000 May;13(5 Pt 1):547-51.
8.Wu CW, Chi CW, Chiu CC, Wu HS, Liu WY, P'eng FK, Wang SR. Can daily dietary arginine supplement affect the function and subpopulation of lymphocytes in patients with advanced gastric cancer? Digestion. 1993;54(2):118-24.
EDITOR'S NOTE: This monograph can be found in The Health Professional's Guide to Dietary Supplements (Lippincott, Williams & Wilkins) by Shawn M. Talbott, PhD and Kerry Hughes, MS.