Thursday, November 22, 2018

Cinnamon, Is it Safe? Not For Everyone.


https://upload.wikimedia.org/wikipedia/commons/thumb/e/e9/Cinnamon_Variaties_-_Robin.jpg/320px-Cinnamon_Variaties_-_Robin.jpg
• It turns out that some people have some genetic differences that might make Cinnamon an unsafe spice for them.

• The idea that the coumarin in Cinnamon is a blood thinner is not true. 

•  All Cinnamons are not alike.

A Review of Cinnamon's Side Effects

Cinnamon is a much used and loved herb. Since recently writing about the study involving a research participant experiencing 4+ edema after ingestion of Cinnamon powder, I have been thinking about all the confusion around Cinnamon and it's safety. I thought it might be beneficial to go over the possible safety issues associated with Cinnamon and attempt to alleviate some of the confusion. Although, we use Cinnamon as a flavoring, and as a medicine, any food, flavoring or medicine can become toxic when used inappropriately. So, let's delve into the sometimes confusing world of cinnamon. The information available is quite conflicting, even in the research world. Consumers, practitioners, researchers - basically, most of us have been confused by the world of Cinnamon in a variety of ways. Lets unravel this confusion to get to the truth.


What Is Being Sold as Cinnamon
I think we have to start by looking at what is on the market called Cinnamon. Cinnamon is a bark that is usually offered as a powder or as quills (rolled up thin inner bark), but it can also be purchased as cut whole bark. It can be one of many Cinnamomum species and they can differ greatly as far as the amount of constituents in them that give them flavor, medicinal effect and side effects.

The kind of Cinnamon most commonly found on the market is Cinnamomum cassia (also called Cinnamomum aromaticum). Common names for it are Cassia or Chinese Cinnamon. This is the type grown and produced in China and Indonesia. It is the cheapest Cinnamon on the market and quite spicy and therefore the most commonly purchased Cinnamon. Cinnamomum verum (also called Cinnamomum zeylanicum) carries the common name of true Cinnamon tree or Ceylon Cinnamon tree or Sri Lanka Cinnamon.  Records show "true Cinnamon" was confused historically with Cassia or Cinnamomum cassia. The spice traders were careful to keep its origins a secret so they could have control of the Cinnamon market. They did not actually want it known that the delicate, sweet Ceylon Cinnamon was from Sri Lanka and Southern Indian areas. (It is native to India, Sri Lanka, Bangladesh and Nyanmar.) There continues to be confusion about Cinnamon species among consumers to this day. You will see many non-Cassia Cinnamons being called Cassia on the market. Additional Cinnamon species you will see on the market are Cinnamonum burmannii (Korintje, Padang cassia, or Indonesian Cinnamon), Cinnamonum loureiroi (Saigon Cinnamon, Vietnamese cassia, or Vietnamese Cinnamon). There are others, but these are the ones we most commonly see.

These Cinnamons differ slightly in taste. Ceylon or "true" Cinnamon is lighter in color than the others and has a sweeter, milder, fragrant, less harsh taste and contains less coumarin.  Sometimes it is listed as Sweet Cinnamon, but I have seen other species listed as Sweet Cinnamon also. Usually when used in cooking, more of it is needed to get a similar flavor as one of the stronger tasting Cinnamons, such as Cassia. Many people think Vietnamese Cinnamon has a more complex taste in comparison with others. Both Cassia and Vietnamese Cinnamon have been found to have more flavor than most other Cinnamons.

Constituents 
Some of the more important medicinal constituents found in Cinnamon are procyanidinoligomers, various cinnamaldehydes, coumarin, trans-cinnamic acid, catechin, epicatechin, coumarin and eugenol. One important difference between Ceylon cinnamon and the other Cinnamons such as Cassia, is the coumarin content. You will soon see how this may be important when it comes to side effects.

Actions
Astringent, Diaphoretic, Carminative, Hemostatic, Antiseptic, Flavoring,  Antibacterial, Antifungal, Gastrointestinal tonic, Analgesic, Hypoglycemic,  Antioxidant, Anti-inflammatory, Antidiabetc, Anticarcinogenic.

Side Effects And Contraindications
Cinnamon as with many spices may be contraindicated in pregnancy due to the possible emmenagogue effect. (Check with your practitioner.) Due to its ability to lower blood sugar it may exacerbate low blood sugar in hypoglycemics as well as add to the hypoglycemic effects of people taking hypoglycemic drugs.

Doses exceeding 2 grams of Cinnamon have been reported to be narcotic and may cause convulsions, delirium, hallucinations and death. However, research 2003 claimed to safely used Cinnamomum cassia in as much as 6 grams and listed no adverse effects, although I noted the research did not test for liver and kidney damage and had only 60 people. Another small group was given 6 grams "safely" but again did not test liver and kidney function. A larger group needs to be tested, along with monitoring liver and kidney function, and for a longer period of time. Research using a different species called Cinnamomum verum has been tested longer term with an extract that was equivalent to 6 grams of raw Cinnamon powder and it was shown to be non-harmful to the liver and kidney. As you will soon see though, this species has much less coumarin than Cinnamomum cassia and is considered safer.

Part of the issue is that Cinnamon species differ from one another in the amount of constituents that can cause toxicity, but additionally different samples taken from the same tree bark have even contained different amounts of these constituents. So, when it comes to knowing how much whole herb is safe, we really can't say for sure. We can only extrapolate from the clinical research studies we have available. There are safety studies with animals, but this does not tell us what will happen in humans. It just gives us inklings of an idea, as there are similarities and differences between our biotransformation (detox) systems and those of the animals tested.

The Cinnamon constituents most notable for toxicity are coumarin and cinnamaldehyde. Coumarin has been such a concern (due to animal studies largely) that it is regulated in some countries. Both of these constituents also have medicinal effects. What doses cause toxicity of these constituents has not been properly discerned, and coumarin appears to effect some people more than others. A review of safety concerns for these two constituents follows. However, I want to remind you that constituents in a plant act differently by themselves than they do in concert with all the other constituents in a given plant. I will say more about this in regards to Cinnamon, later in this article.

Cinnamaldehyde
The aroma and flavor of cinnamon comes from its essential oil that makes up 0.5 to 1% of its composition, and a constituent in the oil, called cinnamaldehyde is about 50%-95% of the essential oil from the bark (I specify bark, as other parts of the plant are also used, but the bark is what is mainly consumed as spice and medicine on the market) depending on the species of Cinnamon. Cinnamaldehyde is one of the constituents responsible for the health effects of Cinnamon. 

Cinnamomum cassia barks contain high contents of cinnamaldehyde (13.01−56.93 mg/g). The highest content of cinnamaldehyde (up to 93.83 mg/g) was found in debarked cortex (inner bark), which is traditionally thought to be the best quality and what is sold in herb shops. In contrast, the researchers found other Cinnamomum species, C. wilsonii Camble, C. japonicum Sieb., C. mairei Levl. and C. burmanii, contained lower contents of cinnamaldehyde. 

A 2018 research review of adverse events resulting from cinnamon use reported gastrointestinal disorders and allergic reactions as the most frequently reported side effects or what some call allergic reactions.  These effects are thought to be due to the cinnamaldehyde content in the Cinnamon. These reactions include mouth sores, which are often from eating excessive Cinnamon, although some people may be more sensitive to cinnamaldehyde than others. In addition to mouth sores, other symptoms of a cinnamaldehyde reaction include tongue or gum swelling, a burning or itching sensation and white patches in the mouth. While these symptoms aren’t necessarily serious, they can cause discomfort. This cinnamon contact stomatitis (inflamed mouth and lips, with or without ulcers)  is usually from an individual reacting to cinnamon or cinnamon flavored gums, candies, mouthwash, toothpaste or other foods. They will recover completely and quickly within a matter of days after discontinuing all sources of Cinnamon.

Skin irritation can take place from direct application of Cinnamon to the skin and again is thought to be due to cinnamaldehyde. It may cause a red, itchy rash. For most people it is just annoying, but some people have stronger reactions than others.

A study published in 2007, found the median lethal dose value (LD50) of orally administered cinnamaldehyde  in rats was 1850 ± 37 mg/kg. Be aware that this is not a human study, but a rat study. Studies on animals can not be assumed to be the same for humans. It just gives us ideas of safety or harm.

Coumarin - 2H-1-benzopyran-2-one
Coumarin is aromatic. It gives cut hay that wonderful aromatic smell that many people notice. Coumarin's from plant are used in soap, perfumes, fabric softener, some alcoholic drinks and the tobacco industry. Coumarin can be in high levels in Cinnamon as well as Sweet woodruff, and Tonka beans which are also used as a flavoring. It can be found in smaller amounts in a variety of foods. Coumarin has been studied for its health benefits, but it also has received a lot of concern around it's possible toxicity.

Research has shown that the coumarin content of cinnamon bark varies by cultivation site. It has also been reported that there is as much as 21 times difference in the coumarin content of Cassia varieties from different places of cultivation and that some Cinnamon species do not contain coumarin. 
 
Research (mostly in animals) has found that eating too much coumarin may harm the liver, the kidneys and increase the risk of cancer. Studies  in rodents have found that large doses of coumarin can cause cancerous tumors to develop in their lungs, liver and kidneys. However, the fact is that this research  on rats and mice makes it hard to extrapolate to humans since they metabolize coumarin differently than most humans (there is even some genetic difference in humans).  

I would also point out that it is possible that other constituents in whole Cinnamon such as cinnamaldehyde may protect the body from some of the organ damage that might otherwise occur with coumarin. Other constituents such as cinnamaldehyde are antioxidants and have been theorized to have a protective effect. This is why the sum of the individual parts in a whole plant is very different than the individual constituents on their own.

Liver damage: There is credible evidence of coumarin causing liver toxicity but this is largely in rats and a small subset of the human population. In fact in a 1989 study of 2173 patients treated with coumarin in a clinical trial, only 0.37% of them developed elevated liver enzymes during the study. We have learned more recently that there are a small number of sensitive people who have been noted to have liver damage from large doses of cinnamon. Although, not confirmed yet by research, it appears to specifically be a problem for people with a genetic variation of CYP2A6. This variation has at this point been found to be more common in  Asian populations. Coumarin appears to have the potential to cause hepatotoxicity in this subset of people who have insucient CYP2A6 activity to break coumarin down into safe catabolites. Unfortunately, the association between hepatotoxicity and CYP2A6 genetic polymorphism has not been investigated and really needs to be. I will tell you what appears to be going on from the available research so far.
 
Most people's biotransformation (detox) system alters ingested coumarin to 7-hydroxycoumarin and its byproducts. These compounds are nontoxic and are excreted without harm. A reduction in CYP2A6 activity will lead to shunting of coumarin into other metabolic pathways. For instance, coumarin is metabolized by CYP3A4 to form 3-hydroxycoumarin, the major metabolite in mice and rats. It has been shown that an increase in the 3-hydroxycoumarin ratio is associated with an increased production of the significant cytotoxic product o-hydroxyphenylacetylacetaldehyde (o-HPA), suggesting that a shunting of coumarin metabolism away from 7-hydroxylation is the cause of the toxicity. Some people with insufficient cytochrome P450(CYP)2A6 have a predominant 3-hydroxylation metabolic pattern or are slow metabolizers, and this can lead to liver damage. I also have to wonder if we will eventually find these slow metabolizers of coumarin will also be predisposed to other damage from insufficient CYP2A6 in other organs such as the kidney, lungs and intestines with excess ingestion of coumarin containing plants. 

Not only is the damage to the liver from coumarin seen in rats and much less often in humans, but whole herb Cinnamonum cassia which contains quite a bit of coumarin has actually been shown to protect rats from toxin induced  liver damage as well as kidney damage. 
 
Kidney damage: Although coumarin may be able to cause kidney damage when studied as a single constituent, we can't say that the whole herb or extracts will do the same thing. In fact Cinnamon and it's constituent cinnamaldehyde may have protective effects upon the kidney. Cancer: Although there is some research to support the possible carcinogenic activity of coumarin. Evidence for Cinnamon causing cancer is not so evident. In fact, Cinnamonum as a whole herb, as well as various constituents in Cinnamon have been found to be anticarcinogenic.      Coumarin Never Shown to be a Blood Thinner: There is tremendous confusion around coumarin being a blood thinner. You will see many research articles, and herbal/health articles listing coumarin as a blood thinner, but to my knowledge coumarin has never been shown to act as an anticoagulant. I have searched for proof of coumarin's use as a blood thinner and simply can't find it. How this incorrect information has taken root is as follows: Fungus (such as Penicillium and Aspergillus sp.) that grows on plants can change coumarin into a mycotoxin that can thin the blood, and these mycotoxins have then been eaten by farm animals which have hemorrhaged, some to their death. This is one way the confusion exists. This blood thinning of the mycotoxin has been blamed on coumarin due to people thinking it was a reaction from the plant, and not realizing it was a fungus created mycotoxin that caused the anticoagulant activity. This mycotoxin is called dicumarol. However, the actual coumarin itself has not been shown to act as a blood thinner. Additionally, drugs that are synthesized from coumarin are used as blood thinners. These drugs get confused with coumarin, so let's examine that closer.
A synthetic coumarin analog is used in the synthesis of synthetic anticoagulant pharmaceuticals similar to the dicumarol created by the fungus from natural coumarin. The most well know synthetic anticoagulant made from a coumarin analog is warfarin (Brand name Coumadin). You can see how the drug name Coumadin could be counfused with coumarin. Even research articles will list the name coumarin when they mean Coumadin.
Due to the animal research showing coumarin is hazardous, there are restrictions in some countries on how much coumarin is allowed in food items such as Cinnamon. The tolerable daily intake for coumarin in Germany is 0.1 mg per kg of body weight or 6.8 mg per day for a 150-pound person. This is based on a subacute chronic toxicity study for dogs, as they are considered the most sensitive to coumarin. However, trying to figure out how much coumarin is actually in a given amount of Cinnamon is fairly impossible. To give you an idea of how much variation can occur, the BFR claims Cassia Cinnamon on average contains 2.1-4.4 g of coumarin per kg of Cinnamon powder. (However, the highest measured levels were as high as 10000 mg ((10 g)) of coumarin per kg of Cassia Cinnamon.) which means 1 teaspoon of Cassia powder would contain around 5.8-12.1 mg of coumarin. This is above the Tolerable Daily Intake (TDI) for coumarin of 0.1mg/kg body weight/day recommended by the European Food Safety Authority (EFSA). The BfR in its report specifically states "Ceylon cinnamon only contains low levels of coumarin which in the opinion of the BfR are safe in terms of their health effects. Cassia cinnamon contains higher levels of coumarin. For this reason, people are advised, not to consume large quantities of Cassia over prolonged periods of time." From a collection of data available, it appears Cinnamomum verum as having 0.017 g/kg coumarin, while Cinnamomum aromaticum/cassia had 0.31 g/kg, Cinnamomum burmanni had  2.15 g/kg, and Cinnamomum loureiroi had 6.97 g/kg. (Again, remember that these amounts can change from plant to plant and even in the same plant.)    
As you can see Cinnamomum verum or Ceylon cinnamon has a much lower coumarin content than other Cinnamons. You might ask, if you will still get the medicinal results you are hoping for by using this species. Although, Cassia has been largely used medicinally due to it being the main and cheapest form of Cinnamon on the market, Ceylon Cinnamon  has research to support its medicinal activity including a 2017 published article of the first human trials on this species of Cinnamon regarding antidiabetic activity. (Other species also have studies on various health effects.)  It included safety data. I will include a brief review of it here.  
In 2017 Cinnamomum verum (AKA zeylanicum) - Ceylon Cinnamon was used in a study with human diabetics for the first time. They used varied doses up to 500 mg twice per day (1000mg per day) of the powder for a 4 month study. There was no change in kidney, liver function tests, prothrombin time (measures coagulation which of course was normal) or adverse events during the study. 
Safety study of Ceylon Cinnamon: As we noted, Ceylon Cinnamon has been thought to be safer than the other species on the market due to low coumarin levels, and  in this study with 30 adults they wanted to see just how safe it might be. This 3 month study examined a water extract (not the powder, but an extract). The corresponding doses of cinnamon for 1 g, 3 g, 6 g of raw cinnamon was as extract 85 mg (1st month), 250 mg (2nd month) and 500 mg (3rd month). The effects of Ceylon Cinnamon's on the participants was measured each month by examining a variety of lab parameters. The full blood count, kidney and liver function tests and  fasting blood glucose as well as HDL-c, VLDL-d and triglycerides remained in normal range for the 3 months of the study. The participants blood pressured reduced significantly in the first month and stayed reduced the full time. There was a significant reduction in total cholesterol and LCL-c. Four participants had stomach irritation and  two of them stopped the study due to the irritation.       

My Ultimate Take on This Herb Unless, I found I had a CYP2A6 variant (more common if I was Asian), which would not allow me to properly biotransform (detox) coumarin, I plan to keep enjoying Cinnamon in my food. Additionally, I personally feel fine about using it as a medicine should I need it. If concerned about coumarin, I could use the Cinnamomum verum unless I am wanting another species for a particular medicinal reason. In fact, if I want one of the health benefits of coumarin such as using it for lymphadema, I would need to use another species since Cinnamomum verum has little coumarin to speak of. I will continue to watch the research and expect that the whole issue around Cinnamon, coumarin and safety will be resolved, although it may take another five to ten years. It is likely that the other species of Cinnamon will not be harmful in medicinally used amounts, but I don't know that for sure. I would certainly tell anyone with a CYP2A6 variant (or concern they  may have this variant) to remove Cinnamon from their diet to be on the safe side or at least consider only Ceylon Cinnamon. Additionally, if I had a patient who had elevated liver enzymes or elevated kidney indices, I would certainly include checking their Cinnamon intake as one of the many possible causes.   If you are looking for a low coumarin content Cinnamon, Diyesta linked below is a nice organic Cylon Cinnamon  I purchased recently. Yes, I purchase a pound at a time, as I go through that much in a year or less. Plus I can pay the same amount for a small bottle of Ceylon Cinnamon from some suppliers. If you want a small amount of Ceylon Cinnamon, Frontier herbs usually has decent spices for sale. They also have a 1# bag available. The only one I have actually tried below is the first one that is from Diyesta in Sri Lanka.