Tips on Selecting High-Quality Dietary Supplements
A. Ingredient quality
a. Make sure the herb or supplement in the bottle is the plant species or phytochemical that you are looking for, and that it includes the right plant part.
b. It may be useful to get a product that is standardized to contain a specific amount of an active phytochemical
c. Quality seals such as USP (U.S. Pharmacopeia) or NF (National Formulary) given by independent organizations are useful though not absolutely necessary indicators of quality. No quality seals have yet been developed for products that contain multiple herbs or other ingredients, so you should not expect to see seals on these products.
d. Look for the name and contact information of the manufacturer. The company may have information on quality control procedures available by phone or internet. If it is a company whose supplements you have used successfully in the past, this can be a good guide for making choices.
e. Avoid supplements publicized as “miracle cures”, or ones that use testimonials rather than science to back up their use.
f. Organically grown ingredients and wild herbs that give some indication (on packaging or website) of sustainable harvest practices are the best for the environment – and you! You may also want to look for special information such as Kosher processing or vegetarian/vegan capsules.
g. Avoid getting the cheapest supplement you can find. Supplements that are priced much lower than similar products may be of lower quality or have much lower levels of active ingredients.
a. Look for a lot number or batch number on the packaging. This enables the manufacturer to trace products back to their origin. It does not ensure the product’s quality, but does indicate a responsible manufacturer.
b. An expiration date may be useful, and can be used as an indication of freshness, although we do not actually know accurate ways to determine expiration for some types of supplements.
C. Minimum safety information
a. Make sure you understand the dose of the herb or supplement you will be taking, and the instructions for taking the supplement (i.e. should you take an entire dropperful or only a drop or two of a liquid supplement? How many tablets per day and should they be taken with or without food?)
b. Supplements should be tested for toxic substances such as pesticides, lead or mercury and this information should be available on the packaging or the manufacturer’s website. Look for hypoallergenic products if you have problems with food sensitivities.
D. Expanded safety information
a. Look for information about drug interactions or other safety considerations on the supplement package. These would include possible side effects, use during pregnancy, use by children, whether the supplement should be taken with food, etc.
a. Clinical trials are the best indication of whether a supplement is efficacious for a particular condition. The packaging may show data about a clinical trial; you may also be able to find information about whether a particular extract or phytochemical has been clinically tested on the manufacturer’s website
a. One issue with some supplements is whether the tablet can dissolve in the body. Supplements or websites may have information about dissolution or disintegration tests on a supplement.
Assessing Supplement Quality
Keith Block, M.D.,
Why Quality Counts--Understanding Purity and Potency
There are two fundamental issues when it comes to supplement quality: purity and potency. Purity-related concerns have mainly to do with contamination and adulteration. Herbal supplements in particular are prone to become contaminated by bacteria, heavy metals, and drug residues. All three factors can be introduced at various points of the processing of supplements. The health-related concerns are different for each type of
contamination: bacteria might lead to infection, heavy metals to toxicity, and drug residues to untoward physiological effects.
Most of the reported problems stem from the adulteration and contamination of herbal products. For example, herbal producers in
such as lead, mercury, and cadmium.
Some herbal formulas from
methyltestosterone, phenylbutazone, and prednisone. In some countries combinations of what we consider prescription drugs with herbal medicine are in line with local regulations and therefore, including them in herbal supplements is common practice. However, in the
Clearly not all supplements provide what they claim to provide, and some may be so contaminated that they may put your long-range health in jeopardy. Some of the contamination is a byproduct of the way these herbs are handled before they ever hit the marketplace. For example, many of the machines, utensils and brewing containers that are used in processing the herbs may contribute to heavy metal contamination. If the herbs have not undergone proper drying and storage, the crude plant material can become infested with microorganisms that are capable of producing mycotoxins. Several of these
mycotoxins can in turn generate aflatoxins, which have been linked to various cancers.
Given these facts, quality issues must not be overlooked when selecting supplements. One of the ways supplement manufacturers can verify the potency, purity, and bioavailability of their supplement is to have the raw materials independently tested for both purity and potency. Companies that care about their reputations will usually have this testing done ahead of time. Of course, it's important to be sure that the laboratory used for the testing has no ongoing fiscal relationship with the supplement manufacturer or with the supplier of raw materials. This kind of independent verification helps to prevent fraudulent misrepresentation by companies that simply want to promote their product.
Lastly, let's consider the issue of potency. When I use the term potency, I'm referring to two things: (1) the strength and freshness of the supplement, and (2) the quantity or concentration of active ingredients. These factors can vary immensely among supplements with ostensibly the same ingredients but different brand names. Your first line of inquiry should be: Is the main ingredient(s) biologically active and thus likely to confer some benefit? Since potency declines over time, supplement labels should carry
an expiration date-a basic measure of quality assurance. They should also carry warnings regarding potential harmful interactions or side effects-ideally identifying those interactions that would be unique to cancer patients. Unfortunately, most companies do not produce supplements designed specifically with the needs of cancer patients in mind. It is even more reason that I believe physicians and nutrition experts must oversee, examine, and monitor the formulations they advise.
Perhaps the soundest way of ensuring a high-quality herbal
supplement is to use high-quality ingredients – herbs that are grown under
controlled conditions using seeds of a known species and variety of plant;
harvested when their phytochemical contents are most advantageous; processed
quickly, cleanly and efficiently; and maintained under clean conditions while
they are being shipped and incorporated in the process of manufacturing a
supplement. Some companies
specialize in obtaining and preparing herbs in this way, and then preparing
extracts that simply concentrate the entire plant.
In many cases, whole plant
extracts are the best products to use.
They include the full spectrum of phytochemicals in the plant.
If an herbal extract is made using water (or some other solvents), for
instance, only the water-soluble components of the plant will be in the extract.
However, many herbs contain important non-water soluble components, and
these would be missing. You could,
of course, simply take the entire unprocessed herb, but in many instances, you
would need to take a large number of capsules to get as much herb as you need.
A process called “supercritical extraction” –
similar to the process used for decaffeinated coffee but without the use
of problematic solvents – yields a whole plant extract that is highly
concentrated. Some excellent
supplements are made through the combination of careful sourcing of the fresh
herbal material and supercritical extraction.
In general, I advocate the use of whole plants in both herbs and foods,
since these are the closest to the natural forms of plants that humans have been
eating for millennia. However, I
also will use whole plant extracts that have specific compounds of known
biological activity added to them for specific applications.
Standardized extracts are another way that manufacturers approach the problem of quality control. Standardized extracts contain specified amounts of certain named phytochemicals based on what is scientifically thought to be the optimal concentration of the most effective array of phytochemicals. When a supplement is standardized, you can feel more confident that you’re getting what the label says.
Standardization is achieved by several means: by making an extract containing only the phytochemicals that are thought to be effective (active) for a particular condition, by blending herbal extracts; by spiking with the active constituent or by standardizing to what is referred to as a “marker” compound. The marker compound is a phytochemical that is unique to the species of plant that is present in the extract.
By using standardized products, you know with some assurance how much of the
active ingredient is actually present in the supplement. And for some ingredients, it is optimal to use products that are high in specific phytochemicals. Let me give you
an example of how this plays out in my clinical practice. My research team and I have formulated a decaffeinated green tea extract with a very high concentration-standardized to 70 percent of epigallocatechin gallate (EGCG). One gram of the EGCG supplement is equivalent to 35 grams of green tea. Since the typical bag of green tea contains 1.6 grams of tea, a daily dose of our supplement (8 tablets) contains the equivalent of more than fifty cups of green tea. Additionally, in taking this supplement, my patients are able to bypass the stimulating effect of caffeine, normally found in green tea.
If you think potency is not a serious concern for supplement users, think again. Some manufacturers provide chemical analysis of their herbal products, which can give you some confidence in their products. Many supplements have inadequate levels of active ingredients or contain no active ingredients whatsoever. In other cases, the active ingredients are either poorly defined or unknown-which of course takes the onus off the manufacturer.
As a case in point, consider the findings from a study that sampled dozens of different ginseng products. After pooling the results of numerous analyses, the investigators concluded six out of every ten products were deemed "worthless," while one in four contained no ginseng at all. Ginseng is among the herbal agents that have demonstrated anticancer as well as stress-reducing (adaptogenic) value.
The situation with
Echinacea is perhaps the most popular of all herbal agents. Consumer Reports analyzed a dozen echinacea supplements for their phenolic content, since phenols are deemed to be the main active components. The researchers found that the phenolic content varied by more than fivefold in the products they tested. We know from previous studies that high-quality echinacea preparations show a phenolic content of at least four percent. Shockingly, of the echinacea products analyzed in this study, only 17 percent (fewer than one in five) actually met this key criterion for quality.
The three supplements I've just mentioned-ginseng,
part of the manufacturers. Because the manufacture of non-pharmaceutical agents is mostly unregulated, many supplements may not provide what they claim to provide.
Herbs are not the only kind of material used for dietary supplements. Vitamins, minerals and specific phytochemicals extracted from foods (such as beta-carotene) are also important supplement constituents. These phytochemicals can also be synthesized chemically instead of extracted from foods. In general, I would tend to trust natural phytochemical supplements over synthetic supplements, because the latter may tend to have lower potency. Many synthetic beta-carotene supplements, for example, are devoid of actual carotene content, according to my colleague Dr. Kedar Prasad, of the
There is hope on the horizon, though.
In 2007 the FDA published a set of rules for what are called “Good
Manufacturing Practices” for
The Importance of Formulation
An Example--Making Omega-3's Work for You Rather than Against You
When I formulate supplements for my patients, I combine multiple nutrients into a single formula to more effectively target specific mechanisms while making the program more practical. When I first started out, patients found it difficult to take so many individual agents even if I provided them with the right forms and dosing.
Back in the late 1980s, my colleagues and I began to explore and do scientific research using dietary supplements as an integral facet of helping cancer patients maintain their overall health. We began using advanced lab testing to evaluate the blood levels of
various nutrients and phytonutrients in our patients. The results of this testing quickly alerted us to the fact that some supplements clearly were not performing as well as others. These are among the main reasons I started formulating my own supplements. Additionally, the formulations were not designed for cancer patients nor the situations they were facing. We thus decided to seek out a manufacturing facility that meets the FDA standards for making pharmaceuticals. Fish oil supplements are one example
of a quality concern that we had early on and have since addressed. Here's what we learned along the way.
As most food scientists can tell you, the omega-3 fatty acids in fish oil tend to oxidize quite rapidly upon exposure to air or heat-and oxidized fish oil confers few if any health benefits. Also, many of the fish oil products we looked at contained contaminants such as mercury and pesticides. This led us to focus on formulating a fish oil supplement in accord with certain specifications. For example, while investigating the key quality issues, we learned that fish caught in the north
with PCB's, heavy metals, and common pesticides.
We then opted to test each batch of fish oil with an independent laboratory to evaluate the levels of these contaminants. To further ensure that we met certain quality standards, we undertook careful processing of the fish oil using (1) low-temperature purification and encapsulation techniques, (2) nitrogen flushing to reduce the oxidation of omega-3 fatty acids, and (3) the inclusion of antioxidants to further minimize oxidation. We then elected to filter the fatty acids to develop a more pure omega-3 product. Lastly, we decided to enterically coat the fish oil capsules. This process renders them impervious to digestion in the stomach, thus helping avoid the "fishy-smelling burps" that consumers have complained about when taking fish oil and that can be particularly disturbing to cancer patients and others who may have gastrointestinal difficulties due to their disease or medications. I feel confident that this last adjustment has improved the consistency with which our patients take fish oil, and that our healthy obsession with
quality has, in general, earned real dividends in terms of our ability to better serve our patients.
A 5-point System for Assessing Supplement Quality
Since there are currently few enforceable standards on the manufacturing of
dietary supplements, assessing quality largely falls to the consumer.
Not surprisingly, the consumer is often ill-equipped to make such an
assessment since a pharmaceutical and medical knowledge base is essential in
assessing quality. The consumer
needs guidance from physicians, pharmacists and other healthcare professionals
to help separate the quality supplemental products from the poor ones.
It is especially important now for physicians to guide their patients’
use of supplements because more people are using supplements than ever before.
According to one study, about 40% of the population takes vitamins or
minerals and about 15% take an herbal or supplement.
Another study from 1999 estimated the number of Americans using herbals
These numbers are up from about 2.5% of the
· 1. Ingredient quality –includes GAP, GMP as well as adulteration issues
· 2. Stability – ensures proper storage and tracking of the product
· 3. Minimum safety information – provides basic dosing information
· 4. Expanded safety information – provides toxicology, purported mechanism of action, and possible side effects
· 5. Efficacy – shows clinical efficacy and measurable biologic response
1. Ingredient Quality
As discussed earlier, there are currently no
Good Manufacturing Practice (GMP) standards for dietary supplements,
although they are expected shortly.
Similarly, there are no Good Agricultural Practice (GAP – a similar set of
standards for good practices in growing and havesting herbs) guidelines so the
only way to tell if a product is made under a GAP/GMP standard is if the label
states it. The
The part of the plant used in the product needs to be labeled, according to
federal regulations, but the physician must know how to interpret such
information. So for Korean ginseng,
the roots contain most of the ginsenosides, the active component of ginseng,
while the root hairs, the leaves and the stems have much less ginsenosides.
There thus can be considerable variability in the products.
One study looked at 25 different ginseng products in the
Like pharmaceutical products, the efficacy of a supplement relies on its freshness. Assuming GAP/GMP standards were followed, the next step in following the quality trail is to look for evidence of proper storage by the manufacturer, and a manufacturer tracking system so a specific batch can be identified if a problem with the product arises while on the market. The presence of a lot number and formulation number indicate the manufacturer can trace a product back to its origin. Specific recommendations on the label as to proper storage of the product as well as an expiration date for the product are indications the manufacturer is cognizant of freshness and stability issues with the product. While the presence of these elements do not ensure the quality of the product, they do increase the likelihood that the product was responsibly made.
3. Minimum Safety
Government regulation mandates that nutritional information and percent of the Recommended Daily Allowance (RDA) of all ingredients be listed on the product label. While this information may be important for foods, vitamins and minerals, it is often inconsequential for herbals. Many herbals with documented clinical efficacy, like ginseng or black cohosh, do not contain any elements relevant to nutritional guidelines. Additionally, some supplements taken at mega-doses show efficacy not seen at the RDA levels. Appropriate dose and duration of use are also particularly important both for achieving adequate effects as well as for limiting potential toxicities or adverse effects of an agent. Because dosing and duration are dependent on clinical trial data (which is lacking for some supplements), the physician is essential in determining the proper usage for their patients. Of particular interest to the physician is the dosage form of the supplement. For instance, a standardized preparation of a supplement made from dried garlic powder, has a recommended dosage of 200-300mg 3 times daily for cardiovascular health. A preparation of aged garlic extract, however, has a recommended daily dosage of 300-800mg 3 times daily. Similarly a dry, normalized extract of saw palmetto [4:1 (w/w) containing 25% fatty acids] is indicated for prostate health at a dose of 400mg 2 times daily. A saw palmetto tea, however, is not suitable at all because the lipophilic active constituents are insoluble in water.
Duration of use is important both for maximizing the potential helpfulness of
an agent as well as minimizing the potential toxicities that may occur with the
4. Expanded Safety
As more information becomes known about an herbal or supplement through
clinical trials, a physician can guide their patient’s use of such agents based
on more classical parameters of pharmacologically relevant data.
As mechanisms of action are elucidated, and supplement-drug interactions
become better-understood, the physician can identify potential adverse effects
as well as toxicities and contraindications that may occur with that product.
Ephedra has been used for centuries in
The use of Kava for anxiety is another example of how the physician is in a
unique position to identify potential toxicities to their patients.
Kava has been used in the South Pacific for centuries and was considered
to be relatively safe.
While its mechanism is not completely understood, case reports of liver
toxicity began to be reported in the medical literature in the
Another element of significant importance to the physician is the potential
for herb or supplement-drug interactions to occur.
These interactions can often be anticipated based on the mechanisms of
action of each constituent.
Efficacy of any agent is perhaps the most difficult to prove since it
relies on well-designed, randomized, placebo-controlled, clinical studies with a
sufficient number of patients to be able to generalize the results to the
population at large with statistical certainty.
The FDA mandates these trials for pharmaceutical agents before they are
brought to market. The FDA does not
require these trials, however, for herbals or supplements to be brought to
market in the
Of course, the ultimate measure of clinical efficacy is to correlate the
clinical effects of an agent with a measurable level of the agent in the body.
Many of the studies about supplements, however, can show the clinical
efficacy of a product but not the pharmacologic mechanism of the response.
These exact mechanisms remain elusive because many supplement products
have multiple active components working synergistically or concurrently in the
concept is quite different from most pharmaceutical agents which are
single-entity products that work primarily at one particular target.
Consequently, one needs to approach standard drug metabolism parameters
from a slightly different view. For
One problem with some supplements is that they do not dissolve in the stomach. Clearly if a tablet doesn’t even dissolve, it is unlikely that your body will adequately absorb the herbal ingredients. Dissolution and disintegration studies of a particular product can show that the dosage form is appropriate for the herbal or supplement used. These studies indicate whether a product’s active components are appropriately being made available to the body when in that dosage form.
There are other aspects to bioavailability. Some phytochemicals (or medications) are simply not absorbed very well by gastrointestinal tract. There are ways to get around these problems. For instance, it is known that eating some kind of fat or oil wilth carotenoids (red or orange phytochemicals such as beta-carotene or lycopene) improves their absorption. You may thus see instructions to take certain supplements with meals (although sometimes instructions to take supplements or medications with meals are simply to prevent stomach upset) In some cases, manufacturers will put specific substances into supplements, such as bioperine, a pepper extract, to help optimize your ability to absorb them.
Some new ways of formulating supplements also improve bioavailability, in particular the use of nano-technology or liposomes, which “package” supplements or phytochemicals in extremely tiny molecular “envelopes” that enter cells more easily. Supercritical extracts (see above) provide highly concentrated herbal extracts that enable the user to take high doses of an herb in a small number of capsules. One of the well-known strategies for regulating the availability of a supplement is the use of timed-release formulations. Familiar to many people from their use in medicines, these formulations are especially useful in cases where a supplement needs to be available to the body throughout a long portion of the day. An example would be timed-release capsules of melatonin, a sleep aid.
Resources for Credible Herbal/Supplement Information
As more alternative therapies are explored in clinical trials and used by patients, the physician is faced both with having to assess the validity of the evidence for that therapy as well as with recommending a product and protocol to the patient if the treatment appears credible. There are several places one can look to find concise information about a botanical supplement. This brief list of sources is evolving, and new credible sources are being compiled as more clinical evidence is validated.
· The Complete German Commission E Monographs – Therapeutic Guide to Herbal Medicines by Blumenthal M, Goldberg A, Busse WR, Gruenwald J, Hall T, Riggins CW, Rister RS (eds.)
This book is an English translation of the standard European reference for all herbals.
· The ABC Clinical Guide to Herbs by Blumenthal M.
This book is unique in that it provides a list of all brand-name products used in various clinical trials. This list is particularly useful since all products used in clinical trial must meet current GMP standards, and are thus more likely to be quality products. The book includes concise monographs of about 40 commonly used herbal supplements. It also briefly summarizes the current clinical evidence that supports or refutes the purported claims of the herbal.
· www.naturaldatabase.org (Natural Medicines Comprehensive Database) and www.naturalstandard.org. (Natural Standard) are subscription sites that provides a comprehensive list of both herbal and supplement monographs linked to primary literature that supports or refutes purported claims. They are available by subscription. Monographs developed by the Natural Standard staff are also available at www.medlineplus.gov under the “Drugs and Supplements” link.
www.mskcc.org/mskcc/html/11570.cfm - Operated by
· www.herbalgram.org – A site run by the American Botanical Council, a not-for-profit organization that provides a wide variety of types of information on herbal medicine. The publication HerbalGram, available from the website, also provides interesting articles and research reviews on a variety of topics.
· www.herbmed.org – A site operated by the Alternative Medicine Foundation, a not-for-profit organization that provides monographs of 20 herbs free-of-charge and a more comprehensive list with on a subscription or pay-per-access basis. The monographs summarize clinical data on an herbal and link to the primary literature.
Dietary supplement use continues to increase8 at a time when the clinical efficacy of many agents are being validated.36-38 Self-regulation and impending FDA legislation are producing many more quality supplement products. It is time for the medical community to help guide their patients’ use of supplement products. Healthcare professionals are in a unique position to evaluate both the quality and efficacy of supplement products so they can confidently advise on the rational use of such products. When used properly, these products can be a powerful tool in increasing the health, benefit and quality-of-life of many patients. Conversely, these products can cause significant harm when used inappropriately without supervision. The physician can influence which extreme predominates. The medical community can take back this responsibility and positively influence their patients’ lives.
Steven Silverstein, Pharm.D., is responsible for a preliminary draft of parts
of this paper, written when he was an intern at the
Kaufman DW, Kelly JP, Rosenberg L, Anderson TE, Mitchell AA.
Recent patterns of
medication use in the ambulatory adult population of the
 Gilbert L. 1999 Healthfocus trend
 Eisenberg DM, Davis RB, Ettner SL, Appel S, Wilkey S, VanRompay M, et al. Trends in alternative medicine use in the United States, 1990-1997: results of a follow-up national survey. JAMA 1998;280:1569-74.
Eisenberg DM, Kessler RC, Foster C, Norlock FE, Calkins DR, Delbanco TL.
Unconventional medicine in the
 Awang D. The anti-stress potential of North American ginseng (panax quinquefolius). J. Herbs, Spices & Med Plants 1998;6(2):87-91.
 Srisurapanon S, Apibal S, Siripol R, et al. The effect of standardized ginseng extract on peripheral blood leucocytes and lymphocyte subjects: a preliminary study in young healthy adults. J Med Assoc Thai 1997;80:S81-5.
 Pharmacopoeia of the People’s
 Vulcan V, Sievenpiper J, Wong J. American ginseng (Panax quinquefolius) attenuates postprandial glycemia in a time-dependent but not dose-dependent manner in healthy adults. Am J Clin Nutr 2001;73:753-8.
 Bone K. Ginseng – The Regal Herb, Part 1. MediHerb Pro Rev 1998;62:1-4.
 Mediherb. Eleutherococcus – an herbal adaptogen, part 1. Mediherb Professional Newsletter 1993:36.
Practical Guide to Natural Medicines.
 Harkey MR, Henderson GL,
Gershwin ME, Stern JS,
 Bank W.
Medicinal plant; rescuing a global heritage.
 Soldati F, Tanaka O. Panax ginseng: relationship between age of plant and content of ginsenosides. Planta Med 1984;50:351-2.
 Warshafsky F, Kamer RS, Sivak SL. Effect of garlic on total serum cholesterol – a meta-analysis. Ann Intern Med 1993;19(7 pt 1): 599-605.
 Steiner M, Khan AH, Holbert D, Lin RI-S. A double-blind crossover study in moderately hypercholesterolemic men that compared the effect of aged garlic extract and placebo administration on blood lipids. Am J Clin Nutr 1996; 64(6):866-70.
 Blumenthal M.
The ABC clinical guide to herbs.
 Bratman S, Kroll D.
The Natural Pharmacist.
Clinical Evaluation of Medicinal Herbs and Other Therapeutic
 Hypericum Depression Trial Study
Group. Effect of Hypericum
 Blumenthal M, Busse WR, Goldberg
A, Gruenwald J, Hall T, Riggins CW, et al.
(eds). The Complete
German Commission E Monographs – Therapeutic Guide to Herbal Medicines.
 Huang K.
The Pharmacology of Chinese Herbs, 2nd ed.
 Blumenthal M, King P. Ma Huang: ancient herb, modern medicine, regulatory dilemma. HerbalGram 1995;34:42-3.
 Chang H, But P (eds.).
Pharmacology and applications of Chinese materia medica, vol 1.
 Leikin J, Klein L. Ephedra causes myocarditis. J Toxicol Clin Toxicol 2000;38(3);353-4.
 FDA website. Final rule declaring dietary supplements containing ephedrine alkaloids adulterated because they present an unreasonable risk. Available from url: http://www.cfsan.fda.gov/~lrd/fr040211.html.
 Singh YN, Blumenthal M. Kava: an overview. HerbalGram 1997;39:33-57.
 Roby CA, Anderson GD, Kantor E,
 Moore LB, Goodwin B, Jones SA,
 Gordon JB.
 Tatro DS.
Drug interactions with
 Linde K, Ramirez G, Mulrow C,
Pauls A, Weidenhammer W, Melchart D.
 Wilt TJ, Ishani A, Stark G, MacDonald R, Lau J, Mulrow C. Saw palmetto extracts for treatment of benign prostatic hyperplasia: a systematic review. JAMA 1998;280(18):1604-9.
 Brockmuller J, Reum T, Bauer S. Roots I: hypericin and pseudohypericin: pharmacokinetics and effects on photosensitivity in humans. Pharmacopsychiatry 1997; 30 (supp 2):94-101.