As you can see, the list of available documents is quite extensive. It is available for members of AHPA (base-level membership for a small-scale manufacturer is $1,000 per year. AHPA is a fantastic organization. $1,000 is a lot of money).
Another development is that I will no longer be posting updates and documents at this site, but rather at a new dedicated site where you can find all previous information and also future updates. Find it here:
Hopefully this will be a more practical way for us to communicate about this. Over the next few weeks, I will be reaching out to folks who have expressed interest in helping, to make them contributors to the site and allow them to edit and add material as they see fit. There are a few items I might suggest putting on our agenda and to-do list for this project:
- live online forum discussion to help us meet, define the work, and agree on goals
- working through explaining the pieces of cGMP compliance (more documents and voice-overs of why they are structured the way they are, and how to customize them for your own business)
- the problem of testing, and its cost: even a testing program that takes random annual samples (which requires some baseline level of confidence in raw materials and in-house manufacturing, and data to support it) still can run hundreds or thousands of dollars, depending on how many products you make
- the lingering uncertainty around defining identity and strength specifications, and testing for those specs, for a multi-botanical herbal dietary supplement.
I'm taking next week off. Stay tuned at https://sites.google.com/site/gmpopensource/home for further updates in the new year.
When manufacturing any dietary supplement (herbal or otherwise), the guidelines on current good manufacturing practices (cGMPs) require that specifications be established for everything that goes into what you're making. This essentially means that you have to define a few things and set a standard that you find acceptable, and then test the relevant material and record the results of that test. The regulations under 21CFR111 tell us what specifications we need - sort of. Let's take a look.
A great outline of all of 21CFR111 is here:
and, for the details on specifications, see section 111.70:
The key pieces are identity (what is it?), purity (for a raw herb, is it all the herb in question? Is there dirt and/or foreign non-herbal matter?), strength and composition (for a raw herb, this is full-strength 100% raw herb), and contamination.
The identity, purity, strength and composition for whole or cut-and-sifted (NOT powders, which require a microscope) can be assessed through organoleptic testing (using sight, smell, feel, and taste) if conducted by a qualified herbalist. The contamination, unfortunately, requires help. This is even if you get a certificate from your vendor telling you that there is an acceptably low level of contamination, if any. This is one of the big pieces that we still have to solve as herbalists: the cost for contamination testing of each batch of raw material can get steep. Is there a way to consolidate results on lots of herbs so all can benefit and/or spread the costs?
Identity specifications are established in an herb monograph, and there should also be a voucher sample of the herb in question, as well as a sample of the cut-and-sifted material if that's how you purchase it. Additionally, details should be included about potential adulterants, if an herb is known to be adulterated (goldenseal and yellowroot for instance). Rejection criteria - meaning, if you find this you mail the herb back to sender - should also be included.
AHPA has begun to collect excellent information on botanical identity, including microscopic identity. You should visit:
Purity specifications can include details on adulterants, but also a way to assess (and reject if necessary) how much filth and foreign matter is present in a sample.
Contamination specifications include:
- microbiological testing. What's an acceptable total bacteria count? What about yeast and mold? Note that in many cases, bacteria, yeast and mold are a normal part of, say, a fresh berry. Without them there would be no wine. But sometimes there's too much. And certain specific bacteria, like E. coli and salmonella, should never be present.
- heavy metal testing. How much arsenic, mercury, lead, cadmium are in the sample? It's tricky to determine what an acceptable level could be for a raw herb. Additionally, there is good evidence that tincturing actually removes heavy metals from the final product (because most, if there are any, remain in the discarded marc).
- pesticide testing. Our argument so far has been that using certified organic herbs shifts the burden of responsibility to USDA, and that we are not required to test for pesticides. We do use only certified organic herbs. This may or may not be enough - the jury is still out. I'd be curious to hear of other's experience here, especially if there has been pushback from FDA even for those who use certified organic raw material.
AHPA has put out great guidance documents to help define these specifications. For an overview, see:
And, for much more details on heavy metals specifically:
The above is good, but the heavy metals specifications refer to daily total maximum intakes, not how much can be in an herb you're planning to use. This is a complex question that has to do with the weigh-to-volume ratio of your tincture(s), the dose, and how much heavy metal is left in the tincture from the original raw herbs. Working backwards from the daily limits, you can make a case for how much should be present in a raw herb. Here is an example of how to make such a case, and includes the final heavy metal limits:
Heavy metals contamination rationale.
Again, the problem isn't necessarily defining the specification, but testing for it. These tests can get quite expensive. There are ways to reduce the amount of testing you do, especially once you have some data to go on - but getting there can be an overwhelming financial burden. We need to find a way to collaborate on these types of tests - to spread the financial burden and somehow, effectively, share results if we want to support small-scale manufacturers.
What follow are a couple of examples: the first is a raw material monograph (the specifications) for Echinacea purpurea root. The second is a specification sheet, where the results of testing are recorded to ensure they comply with the specifications. A voice walk-through is below as well.
|Full document .pdf file|
|Full document .pdf file|
One note: these are "controlled" documents. They must be signed, dated and approved by whomever is in charge of quality control; revision numbers must be advanced if any changes are made; and they should be "secure" (i.e. not easily tampered with or alterable). Filled-out spec sheets must be in hard copy, filled out in ink, and stored. Until this documentation exists, and is signed off at the bottom, you cannot use the herbs for manufacturing and they should be stored in a designated "quarantine" area (blocked off by fencing, walls/doors, or even tape on the floor to distinguish the area from one of active use).
Finally, one cannot necessarily rely on organoleptic testing unless the person conducting the test(s) is qualified to do so. While you don't have to convince me that you know what dry, cut-and-sifted Echinacea purpurea root looks, smells, and tastes like, you will have to convince FDA. Plus, herbalist qualification does raise some interesting questions: could you tell the difference between E. purpurea and E. angustifolia? Perhaps. What about Actaea racemosa and Actaea pachypoda dry, cut-and-sifted rhizome? It's not always so straightforward. Again, AHPA is doing a great job putting together a lot of the specifications and images necessary for herbalists to conduct these tests (see, for instance, the detailed Actaea racemosa monograph), but unless you are a botanist or pharmacognosist with a degree, you will have to prove to FDA that you can competently identify herbs. Essentially, you have to find a way to "test the tester", or qualify the analyst, who is ensuring that the organoleptic specifications are being met. Here are two document that give an example of how one might do this:
Analyst testing method (how we test our testers)
Analyst testing record (where we record the test results)
Ideally, you will build a testing record that shows you can competently identify all the herbs you use. Now, the question remains: how do you know that the sample you're using as a way to certify the herbalist's skill is actually what you think it is? This requires either the purchase of a validated sample, the assistance of a qualified botanist or pharmacognosist, or validation through an external lab test. This can add extra cost. Is there a way for us to centralize this somehow? Could analyst certification be offered at herb conferences?
Any additional training seminars, certificate programs, or herb schools that you can attend (and collect certificates!) serve to bolster your case that you are, indeed, qualified to conduct these tests. Build a strong case, and identity of raw (non-powdered) herbs can be tested using our senses and good reference materials.
So, specifications need to be developed for everything - including packaging and labels - and you have to maintain a record that you checked everything that comes in against those specifications before using material to make any kind of product that will go to the public. This is a big undertaking. In the coming weeks/months we'd like to share as much of what we have as possible. Hopefully these documents can be edited, improved, and custom-tailored to adapt to different individual situations. But the scope of the project has already outgrown this blog: we need a platform that allows for collaborative sharing, posting, and discussion. So next week, I will provide links to a separate website that will hopefully be more interactive and allow us to leverage the excellent experience and advice, as well as offers for help and contributions, that have been coming our way. Thank you for supporting the FDA cGMP open source project and stay tuned!
**NOTE: all the information presented under the "FDA cGMP compliance open source project" is not intended to be legal advice, nor is it in any way guaranteed that my interpretation of the statute and system for compliance is going to satisfy any individual FDA inspector or compliance officer. These pages are a synthesis of my own understanding of the regulations and how to achieve compliance.
We'll look at the label itself in a bit. First, what about claims on labels? There are two types: ingredient claims (this much Vitamin C, for instance, or these many calories), and structure/function claims ("supports healthy immunity" and other such language). It's rare that herbalists will need to make nutrient claims - but I've included a label for a product that contains some honey, so you can see how to articulate the carbohydrate count on a label. But structure/function claims are a source of perpetual befuddlement. What can be said? What cannot? Are there code phrases or tricks?
I will start by saying that there really aren't tricks. You can't get away with saying "this statement has not been evaluated by the Food and Drug Administration. This product is not intended to diagnose, treat, cure or prevent any disease" and then making any claim you want. You can't say "traditionally used" in front of any claim you want, and think this exempts the language. You can't get tricky and say things like "useful during the cold and flu season", because colds and flus are diseases, and herbs can't be useful during disease season because "useful" can only mean "medically useful" in this context. You can make a claim that a supplement supports the normal, healthy function of an organ, system, process or function of the physiology, provided those processes and functions are part of the normal, healthy course of life. You can also use language that FDA doesn't understand, or considers meaningless - like "enhancing yin" or "unblocking stagnant liver qi".
This is the tricky part. It really is up to FDA to decide what a normal, healthy course of life looks like and I have to say that, based on my experience, it appears FDA (and/or their medical consultant squad) spends a little too much time sitting at desks on the computer, eating a questionable diet, feeling stressed and not sleeping too well. This is in part because anxiety, tension and stress, occasional heartburn, gas, upset stomach, PMS and insomnia are all considered part of a normal, healthy course of life. But I digress.
Blood-based parameters - like blood sugar, cholesterol, pressure etc... - are fair game as long as it is clear that the herbal product "supports healthy blood sugar levels that are already in a normal range" (emphasis mine, and is required). Anything else would imply disrupted blood levels, which means disease. Certainly can't mention diabetes.
I have found the following document very helpful:
It gives a good background on how we got here (namely, the Dietary Supplement Health and Education Act, or DSHEA), which is interesting to read if you like context. But you can also search the document right in your web browser. Try typing in "heartburn". Or "blood pressure". Or "insomnia". Then, try "potency" (improving sexual potency is not an acceptable claim, but improving sexual performance is - poor performance is apparently part of a normal, healthy course of life).
These searches give you ways to approach herbal actions from an acceptable structure-function perspective, and more importantly, if you spend a little time reading, you can get a good sense of what will be acceptable, and what might get you into trouble. There are some tricks - "occasional" heartburn and sleeplessness are fine, but without that qualifier, they are diseases (though of course this wouldn't work for "occasional" migraines). Best of all, FDA explicitly says "this is acceptable" after a good many statements, and you can use these statements as you see fit. Beyond this, you have to prove that a claim refers to supporting something that happens anyway as part of being a healthy human if you want to use it.
All claims - even mentioning the word "immune" in a product name - must have an asterisk next to them. This asterisk must point to the FDA disclaimer somewhere on your label, which must be enclosed in a hairline box: "These statements have not been evaluated by the Food and Drug Administration. This product is not intended to diagnose, treat, cure or prevent any disease."
These regulations around claims apply to print and internet material, too. Brochures, business cards, shelf talkers and sales sheets, catalogs, websites, and social media pages - even, perhaps, audio and video - must all comply (and must include the FDA disclaimer). You can't control what others post on your sites - but don't "like" or acknowledge them. Testimonials, if not properly worded, aren't acceptable either. Personally, this is a big loss: I remember back in the day herb companies often had some of the best information on herbs, their pharmacology and applications, in their print and web media. Now, you can't even post a study that references one of the herbs you use because it's seen as implying that the herb can actually do what it does in the study.
One way around this is to set up, or ally yourself with, a few personal social media pages and weblogs. You can link to these from your product pages, even if these external sites say outlandish unacceptable things like how herbs prevent heart attacks. Some warn that such sites must be "two links" away from your herbal company's website - I haven't seen this distinction in action yet.
Once you have defined what acceptable claims you want to use (and I do recommend connecting with ahpa.org to find a lawyer to review these, if you have the financial means), you are required to submit them to FDA, just to let them know that you're saying herbs do things, within 30 days of beginning sales of the product. Here's an example of what such a letter might look like, including the address to send it to:
Herb Pharm Liquid Herbal Extract Vein Health Letter.
Furthermore, you are required to have files that substantiate the claims you're making: if, for example, your elderberry syrup says it supports the immune system, you should have a file that references actual research and dosing, and/or traditional sources (such as 19th century texts), pointing to elderberry's effectiveness (you just can't ever share any of that information with the public on your website).
How to build such claim substantiation files? In the near future, I'd love to start sharing some of what we've put together and would welcome anyone else's support in this. Perhaps a shared online repository? To a certain extent, some of the files are customized for a particular formula or extraction - but there is still the possibility for substantial overlap. For now, start at Health Canada (in many ways more enlightened on this particular regulatory topic), where monographs on many plants are included with references that back up a range of claims. Note, however, that most of these claims are unacceptable to FDA - such as Ashwagandha's effect as a sleep aid - but you can rephrase it as "helps with occasional sleeplessness" and use the Health Canada reference as part of your claim substantiation.
Now, we can look at the specifics of label regulations themselves. There are rules for how a food label generally, and a dietary supplement label specifically, must be structured. There are also variations in requirements depending on the label size. And there is a specific exemption: if there are no nutrient claims or structure/function claims on the label, and there are no wholesale sales, and total annual sales are less than $500,000 or there are less than 100,000 units of a product sold, then having a supplement facts label is not required. If you want to sell your products through a store or distributor, this exemption is not an option. It really only applies to herb shops, farmer's markets, and direct-to-consumer sales.
General rules on food labeling, including the details on exemptions (found in subsection (j)) are in the Code of Federal Regulations (CFR), Title 21, Part 101, subpart 9 (abbreviated as 21CFR101.9). Find the whole thing here:
Specific rules on dietary supplement labeling are in 21CFR101.36, which is available here:
I'll go over these regulations while looking at some specific label examples, which makes it much more clear. But a few pieces to note:
- less that 12 square inches on a label allows you to use 4.5 point font. Anything bigger than 40 square inches requires 6 point at a minimum for text, and 8 point at a minimum for the serving size text in the supplements facts box.
- note the requirements for hairlines, lines, and columns in the supplements facts box. There are some good examples included in 21CFR101.36
- list plants by common name and include the part (root, rhizome, leaf, seed, flower, etc...)
- many herb supplements only need a proprietary blend listed, along with a symbol pointing to a footnote that says "% Daily Value not established". If you add honey or other sweeteners, you may need to list the carbohydrates/sugars, and perhaps the calories, per serving (if the amount per serving exceeds 1g of carbohydrates, and/or if it exceeds 5 calories). The website nutritiondata.com gives good carb/sugars counts for various foods (and a whole lot of other stuff, here's an example for honey: http://nutritiondata.self.com/facts/sweets/5568/2). Just remember, if your serving is 2ml, and there's less than 1g of carbohydrates in there, you don't have to list them on the supplements facts panel.
So, with a little of the background information available, let's take a look at some example labels for two different sizes of a dietary supplement that also contains a little honey. Because writing it all out would take too long, here is a voice walk-through identifying all the important pieces of a (in this case liquid) herbal dietary supplement:
And here are the labels: first, a larger size with a complete supplements facts panel.
Next, a small size with a "linear" supplement facts declaration (only for labels smaller than 12 square inches, though you could make a case to use this way if it's under 40 square inches and there's no room for a big panel).
Next week we'll start to talk about the ingredients and packaging that go into making dietary supplements: from herbs and other ingredients, to your labels, bottles, closures and seals. We'll look at specifications and hopefully get to some ideas on testing. Another piece to cover (if we can get to it) is getting to know your vendors and "qualifying" them to help streamline future work. As always, questions and comments are welcome and I will do my best to include your experience in the conversation. Anyone who has had labels vetted by FDA inspection or legal counsel is really encouraged to send examples to guido at urbanmoonshine dot com. Thank you!
The landscape of FDA compliance may seem vast, and, indeed, it is. I will tell you, however, that it is not as vast as the landscape of human health and disease: it is much easier to understand than medicine and healing are, and certainly easier to learn. If we are to approach this landscape, which includes forms, research papers, logs and checklists, documentation and reference samples, specifications and lab journals, scales and thermometers, and more, I contend that the best way to begin is to do what herbalists do best: start by finding broad patterns, understand intent and intention, and look at the landscape from high above.
At Urban Moonshine (we make bitters and other tinctures and blends), I can't say we've come to a complete understanding with FDA. The issue of how to identify a liquid formula made from multiple herbs remains. But we have been through every step along the way, and have discovered successful strategies that FDA agrees are valid, and that rely on traditional methods for evaluating and identifying plants - the way herbalists have always done it. These strategies have been tested through multiple inspections. And now it's time for us to share them, share templates of the paperwork, share the research that justifies the specifications we've developed, and help explain what the regulations are, what FDA wants, and how to get there. Not because we've got all the answers, but because we want to open the conversation and create a forum where small-scale producers can get actual news they can use - not just copies of the rules, but actual examples in action. If we can have an ongoing conversation and herbalists across the country can share their collective wisdom, I know we'll have the tools to support anyone who wants to make tinctures for sale in their local communities or across the country.
I won't lie - this is a complicated task, and there are a lot of moving pieces. It's not something you can understand over a weekend and implement with a few days' work. This complexity may have deterred a lot of you, and in the future, may make it impossible for some to keep their heart-centered, small-scale herbal products on the market. FDA welcomes consolidation in the industry - hoping that herbal medicine will become concentrated in the hands of a few, and thus easier to control, easier to oversee.
**NOTE: all the information presented under the "FDA cGMP compliance open source project" is not intended to be legal advice, nor is it in any way guaranteed that my interpretation of the statute and system for compliance is going to satisfy any individual FDA inspector or compliance officer. These pages are a synthesis of my own understanding of the regulations and how to achieve compliance.
Intro to federal regulations
A detailed breakdown of the federal regulations under CFR 21 part 111 (good manufacturing practices), part 101 (labeling requirements), and parts 174-186 (food contact surfaces and packaging requirements) will give the us the tools to critically evaluate a sound master manufacturing record, compliant dietary supplement label, and scientifically valid testing regime.
Herbal Product Manufacturing
The details involved in making a range of herbal products: research, formulation, safety considerations, process control steps required for compliance (FDA cGMPs), extraction, dosage forms, considerations of large-scale operations, packaging supplies.
Facilities and Equipment
We will become familiar both with the basic tools needed for manufacturing and larger-scale equipment such as floor scales, macerating vessels, presses. Maintenance and calibration requirements and tracking.
Records and Paperwork
We will cover the recordkeeping methodology for maintaining a cGMP compliant manufacturing operation, based on requirements from CFR 21.111, and grounded in specific examples currently in use. We will become familiar with creating: master manufacturing records and their associated batch production records; specification sheets for raw, in-process, and finished products as well as eccipients, solvents, and packaging materials; and valid testing methods and documentation.
Marketing, Sales, and DSHEA-compliant language
We will cover design and marketing concepts and suggestions, as well as thoroughly review what constitutes compliant language under DSHEA (regarding promotional material, labels, social media and websites, video, and product trainings).
Quality Control Laboratory
We will become thoroughly familiar with the requirements for identity testing under CFR 21.111, be able to access and compile relevant resources to aid in identity testing (voucher specimens, e.g.), and understand how to contract with third-party laboratories for identity, microbiological, heavy metal, pesticide and herbicide contamination testing.
Orientation to Industry
We will familiarize ourselves with the resources and connections in national professional organizations for the herbal products industry, such as AHPA, as well as legal and consultant resources that might prove useful. Additionally, we will talk about the requirements and practicalities of launching an herbal product: from interfacing with large retailers such as Whole Foods Market, to making barcodes for products, and more.
I am excited to be traveling to the annual American Herbalists' Guild symposium. I'll be presenting a few classes, but below are the notes for a review of the recent research on herbal bitters. Lots of interesting material has come out in the last few years to improve our understanding of how these medicinal plants work in our physiology. I include some practical clinical observations and implications as well.
Summary: Bitter herbs have a well-deserved reputation as digestive aids in most systems of traditional medicine, and in many systems of cuisine. The ability of bitters to support balanced secretion and motility, especially in the gastric phase of digestion, relies on a few important mechanisms that are mediated through taste receptors (T2R family) and involve neuronal, hormonal, and vascular effectors. New research is uncovering additional interesting facts about bitter tasting herbs: first, not all bitter flavors are alike, and a certain degree of variability exists in their effects and spheres of action. Second, additional mechanisms involving adipose tissue, inflammatory mediators, the microbiome, and hepatic glucose balance reinforce the idea that certain bitter herbs may be one of the best strategies for the management of blood sugar and lipid imbalances, the regulation of appetite, and the reversal of the metabolic syndrome.
Background: bitter taste receptors: traditional and modern understanding
The current understanding of our ability to sense taste transcends the classical notions that specific areas on the tongue correspond to specific flavors, or that taste perception is indeed localized to the tongue. Wolfgang Meyerhof studies molecular genetics at the German Institute of Human Nutrition and has provided extensive research into the structure, coding sequences, and function of bitter taste receptors (TAS2Rs, aka T2Rs, a family of G-protein coupled receptors). Some interesting points include the facts that T2Rs present numerous different isoforms, able to sense over 100 different bitter tastants and their combinations [Ref: Meyerhof W, Batram C, Kuhn C, Brockhoff A, Chudoba E, Bufe B, Appendino G, Behrens M. 2010 The molecular receptive ranges of human TAS2R bitter taste receptors. Chemical Senses. 35(2):157-70]; they relay information from the tongue to the nucleus tractus solitarius (medulla) and from there to the hypothalamus using proteins such as alpha-gustducin; and participate in parasympathetic activities such as increased oral and gastric secretions [Ref: Meyerhof, Wolfgang, et al. "Human bitter taste perception." Chemical Senses30.suppl 1 (2005): i14-i15.] More recent research by Meyerhof and others indicates that, unlike most stimulus/receptor pairs in human physiology, the expression of T2Rs increases (to a point) the more stimulus is presented: that is, the more we taste bitter, the more we are able to experience its effects [Ref: Behrens M, Meyerhof W. Bitter taste receptors and human bitter taste perception. Cell Mol Life Sci. 2006 Jul;63(13):1501-9.] What we may, in fact, be noticing is that the human physiology _under_expresses T2Rs until an adequate amount of bitter stimulus is present, at which point a "normal" level of expression is achieved.
Perhaps more interestingly when we consider the inflammatory nature of chronic disease, especially the metabolic syndrome, emerging research is indicating that high levels of pro-inflammatory compounds also serve to _over_express T2Rs, leading to a highly aversive response to even small amounts of the bitter flavor [Ref: Feng, Pu, et al. "Regulation of bitter taste responses by tumor necrosis factor." Brain, behavior, and immunity (2015).] Taste-sensitive cells throughout the body have highly tuned TNF receptors (tumor necrosis factor, a pro-inflammatory compound).
Reducing inflammatory load seems to reduce bitter taste receptor expression, which is of interest when we consider that the effects of phytochemicals associated with bitter taste often are anti-inflammatory.
The neuronal feedback elicited by T2R stimulation (via cranial nerves VII-facial, IX-glossopharyngeal and X-vagus) helps control the cephalic and gastric phases of digestion, coordinating secretion and motility by increasing the former and decreasing the latter. This process has been extensively studied and is well-reviewed by Catia Sternini [Ref: Sternini, Catia. "Taste receptors in the gastrointestinal tract. IV. Functional implications of bitter taste receptors in gastrointestinal chemosensing." American Journal of Physiology-Gastrointestinal and Liver Physiology 292.2 (2007): G457-G461.] The net result is improved molecular breakdown of macronutrients in the chyme that enters the intestinal phase of digestion, as well as slower delivery of those digested products. This underlies the traditional indications for digestive bitters: dyspepsia, indigestion and reflux, gas and bloating. But the slower delivery of metabolized carbohydrates to the small intestine also has a role to play in post-prandial (after-meal) glycemia.
It has been clear for some time that T2R stimulation modulates levels of hormones associated with appetite: ghrelin, a hunger hormone, increases at first. But reduced gastric motility leads to a feeling of fullness, and this, coupled with increased levels of hormones associated with satiety (fullness) such as peptide YY (PYY) and glucagon-like-protein 1 (GLP-1), leads to less caloric intake overall [Ref: Janssen, S. et al. Bitter taste receptors and α‑gustducin regulate the secretion of ghrelin with functional effects on food intake and gastric emptying. Proc. Natl Acad. Sci. USA 108, 2094–2099 (2011).] The modulation of these hormones was long thought to be connected to neuronal reflexes, but emerging research shows that the taste cells themselves function as enteroendocrine cells, are present throughout the GI tract, and secrete appreciable levels of their own hormones into the gastrointestinal circulation. Bitter-tasting substances can harness these enteroendocrine cells and contribute to local secretions that affect absorption, appetite, and the metabolism of fat and carbohydrates [Ref: Posovszky C, Wabitsch M, Regulation of Appetite, Satiation, and Body Weight by Enteroendocrine Cells. Part 1: Characteristics of Enteroendocrine Cells and Their Capability of Weight Regulation. Horm Res Paediatr 2015;83:1-10] and [Ref: Palatini, Kimberly, et al. "Diverse Classes of Bitter Phytochemicals Modulate Carbohydrate Metabolism and Immune Responses through Gastrointestinal Bitter Taste Receptors." The FASEB Journal 29.1 Supplement (2015): 405-5.] Thus, bitters may act directly as endocrine triggers, not requiring intervention by the central nervous system.
Another fascinating result of experimental research underscores yet another effect of herbal bitters. A recent review article by Julie Whitehouse and others [Ref: McMullen, Michael K., Julie M. Whitehouse, and Anthony Towell. "Bitters: Time for a New Paradigm." Evidence-Based Complementary and Alternative Medicine 2015 (2015).], lends evidence to the hypothesis that certain bitters (particularly the more strongly-flavored, classic "eupeptic" herbs gentian and wormwood) increase blood flow to the GI tract. This post-prandial hyperemia is achieved, interestingly, via peripheral vasoconstriction and localized (mediated by enteroendocrine cells again) vasodilation. The overall shifting of circulatory volume can act as a negative cardiac chronotrope and inotrope (reducing frequency and strength of heart muscle contractions), and is most likely the reason (rather than increased tone along the vagus nerve) why this phenomenon has been observed after the consumption of bitters. Practically speaking, this suggests that herbal bitters should include at least one of these classic "eupeptics" for maximal effect - for not all bitter tastants elicit the same effects, and not all reduce ingestion of calories equally, as Lindsay Schier observed [Ref: Schier, Lindsey A., Terry L. Davidson, and Terry L. Powley. "Ongoing ingestive behavior is rapidly suppressed by a preabsorptive, intestinal “bitter taste” cue."American Journal of Physiology-Regulatory, Integrative and Comparative Physiology 301.5 (2011): R1557-R1568.]. Additionally, Whitehouse notes that the vascular shift is almost instantaneous (within 5 minutes) after T2Rs in the tongue are stimulated by strong bitter flavors. This implies that one can take bitters before, during, or even after a meal and that the effects can still be beneficial (consuming them 10-15 minutes before eating is not necessary).
Clinical implications: Appetite, glycemia, lipidemia, hypertension and the metabolic syndrome
It appears that our ability to detect and respond to bitter tastants such as those found in bitter herbs is variable, and connected to the internal and external environment. This is the first step in realizing their therapeutic potential: as we age, the expression of T2Rs decreases naturally, and sometimes (in the absence of any bitter stimulus) appears to decrease beyond "normal" expression. This "normal" level can, however, be restored by applying regular bitter taste stimuli. The "bitter deficiency syndrome" hypothesized by James Green in The Male Herbal (J. Green, 2007) has indeed been documented. Women [Ref: Feeney E, O'Brien S, Scannell A, Markey A, Gibney ER. 2011 Genetic variation in taste
perception: does it have a role in healthy eating? Proceedings of the Nutritional Society.
70(1):135-43.] and children [Ref: Negri, Rossella, et al. "Taste perception and food choices." Journal of pediatric gastroenterology and nutrition 54.5 (2012): 624-629.] have much lower levels of obesity when they perceive higher levels of bitterness. Additionally, individuals with high bitter sensitivity have improved blood glucose control, as extensively investigated by Cedrick Dotson at the University of Florida [Ref: Dotson, Cedrick D., et al. "Bitter taste receptors influence glucose homeostasis." PloS one 3.12 (2008).].
The intersection between bitters and inflammation is of particular interest, as is the potential for a post-prandial GI hyperemia (and a resultant reduced load on the heart and arterial system). First, a strong aversive response to bitterness by an individual who has little experience with the flavor may be indicative of a high background level of pro-inflammatory compounds such as TNF. As the aversion decreases, one could expect that the cholagogue, GI anti-inflammatory, hepatic "cooling" effect might be contributing to reduced inflammation (an interesting balance point between increased expression through T2R stimulation and decreased expression via reduced TNF). Second, reduced inflammation plus reduced cardiovascular load and stress are essential components to any therapy designed to address the metabolic syndrome - and through a wide range of mechanisms, bitters appear to do just that. The connection between the bitter flavor and the heart in some traditional healing systems is of note here, as well. Kimberly Palatini's research, mentioned above, suggests that bitters modulate immune responses in the GI tract and in the physiology overall - while balancing and regulating every aspect of carbohydrate absorption and metabolism, increasing glucose tolerance and insulin sensitivity. Of course, improved insulin sensitivity is a direct consequence of reducing high levels of pro-inflammatory compounds: TNF, as well as series-2 prostaglandins, have all been linked to insulin resistance.
Regulation of appetite, leading to the epidemiologic results observed (lower obesity rates), occurs by a variety of mechanisms. The first is related to motility: through cranial nerve feedback, bitters delay gastric emptying leading to a more rapid sensation of fullness. But just as importantly, wide-ranging effects on satiety, appetite, and carbohydrate metabolism, storage and processing are mediated through enteroendocrine cells - which turn out to be sophisticated "tastebuds" with chemoreceptors on the luminal side and the ability to secrete hormones on the basolateral side. T2Rs are found on P/D cells in the stomach, which secrete hormones involved in fat metabolism and insulin sensitivity (increasing both); on I cells in the duodenum which reduce food intake and stimulate CCK; and on the all-important L cells in the small and large intestines, which secrete PYY (satiety) and GLP-1 (insulin sensitivity) [Ref: Posovszky, Carsten, and Martin Wabitsch. "Regulation of appetite, satiation, and body weight by enteroendocrine cells. Part 1: characteristics of enteroendocrine cells and their capability of weight regulation." Hormone Research in Paediatrics 83.1 (2015): 1-10.]. The recent research and potential of bitter tastants in regulating appetite, obesity and the metabolic syndrome are well-reviewed by Sarah Calvo and Josephine Egan in Nature Reviews [Ref: Calvo, Sara Santa-Cruz, and Josephine M. Egan. "The endocrinology of taste receptors." Nature Reviews Endocrinology 11.4 (2015): 213-227.].
And while bitters have important effects on preventing (and perhaps treating) insulin resistance and diabetes, as we have seen from the mechanisms above, I have also seen them correct episodes of transient, non-emergent hypoglycemia on many occasions. Since hypoglycemia in a non-insulin-dependent patient may actually be evidence of disregulated glucose homeostasis and metabolism (a consequence of insulin over-secretion earlier), this does not come as a surprise. Another mechanism whereby bitters correct transient hypoglycemia may involve "tricking" the hypothalamus into believing food is being consumed. This effect may seem like a simple novelty, but it becomes very clinically relevant when you consider the intense sugar cravings experienced during these episodes. If we had a tool to trick the hypothalamus into believing the craving had been satisfied, our patients could make more rational judgements for nutrition (nuts or other sources of fat and protein). Bitters can provide just such a tool.
T2R receptors, and enteroendocrine G-protein-coupled receptors in general, are receiving sustained attention as potential targets for reversing insulin resistance. Exciting research is coming out of Cedrick Dotson's office (mentioned above), who is stimulating T2R receptors with bitter tastants and comparing the insulin-sensitizing effects to the opposite effects found by stimulating sweet taste receptors (T1Rs) [Ref: Dotson CD, Vigues S, Steinle NI, Munger SD. T1R and T2R receptors: the modulation of incretin hormones and potential targets for the treatment of type 2 diabetes mellitus. Curr Opin Investig Drugs 2010; 11: 447–454.].
Finally, many bitters (especially the more "nutritive" bitters, such as dandelion, chicory, elecampane, angelica and burdock) possess appreciable quantities of pre-biotic starches and can deliver these important nutrients when consumed at clinically relevant doses. Oligosaccharides such as inulin can have useful regulatory effects on bowel function, and over time contribute to lower blood glucose, lower lipid levels, and better satiety [Ref: Nishimura, Mie, et al. "Effects of the extract from roasted chicory (Cichorium intybus L.) root containing inulin-type fructans on blood glucose, lipid metabolism, and fecal properties." Journal of Traditional and Complementary Medicine (2015).]. This may be in part due to mechanical effects (such as an osmotic laxative effect), but may also be due to changes in enteroendocrine cell hormone production associated with a shift in microbial populations. A fascinating study by Patrice Cani hinted at just this type of effect in a small (n=10) group [Ref: Cani, Patrice D., et al. "Gut microbiota fermentation of prebiotics increases satietogenic and incretin gut peptide production with consequences for appetite sensation and glucose response after a meal." The American journal of clinical nutrition 90.5 (2009): 1236-1243.] As Steven Abrams noted, this effect is best observed with long-term, habitual use: prebiotics, when combined with calcium (see dandelion root), reduce body mass index better than a placebo control (n=96, one year)[Ref: Abrams, Steven A., et al. "Effect of prebiotic supplementation and calcium intake on body mass index." The Journal of Pediatrics 151.3 (2007): 293-298.].
Conclusion: The digestive-enhancing effects of bitters are well documented, but may be just the beginning of what these traditional preparations have to offer. When consumed in a formula that includes both "eupeptic", strong bitters such as gentian and wormwood, and "nutritive" bitters rich in pre-biotic starches, and taken habitually in material doses, they exert clinically relevant effects on the metabolic syndrome. Appetite, carbohydrate and lipid metabolism all are regulated. Inflammation and cardiovascular load are reduced. Bitters accomplish this through a variety of mechanisms, including neuronal, endocrine, immunologic, and vascular. They most likely need not be consumed too far ahead of a meal, but at any point before, during, or after, and at relatively high doses for the most substantial effects. Given the resurgence of interest in these traditional preparations from those well-versed in the beverage alcohol and cocktail world, we as herbalists may have at our disposal a powerful, flavorful tool for addressing obesity and the metabolic syndrome - one our patients can relate to, and easily incorporate into their lives as a daily habit.
The great blue heron, so still, is like
a standing piece of driftwood, silver-gray cyan,
like when wood sees the pond water too long
and then, pushed up by a frost heave,
sun-bleaches and molders, gathering color.
Her neck feathers are fine grain exposed by years,
the pith and heartwood interweaving,
immobile, strong, fixed quiet to watch.
But when the neck coils down to spring
and wings open, stretching out tips
to catch sun rays in between,
you can feel the air compress
and watch her rise
as if a cord had lifted her from the granite
that lies half sunk beneath the glassy surface.
In my time I too
hope to rise that way,
fast and light and lifted,
not like the loons, who cry and flap,
and beat the water,
needing their slow, heavy ascent
to raise red eyes over the treeline.
"The house is like a dark womb - and heavy, smoky - with a giant red eye at its core."