Order Matters

By Jacob Schor, ND

Photo by Kanko* via Flickr, used under the Creative Commons License.

If order matters, what comes first?

The implications of a study published way back in February in Clinical Cancer Research have been stewing around in the back of my mind. It’s one of a growing cascade of studies in which researchers at fairly mainstream medical institutions reveal that they’ve been playing with stuff that’s standard fare on a naturopathic doctor’s dispensary shelves.

In this instance we are talking about researchers from the Mayo Clinic in Minnesota playing with various combinations of curcumin, an extract of turmeric and green tea, and seeing how they affect lymphocytic leukemia cells.

As much as we still occasionally hear and read the myopic criticisms of our profession that claim our therapies are not backed by research, this study is just one of many. A PubMed search just now of the National Library of Medicine’s published scientific literature on curcumin and cancer yields a list of 1,265 articles. A search on green tea and cancer yields 1,338 published papers in the peer reviewed journals.

This particular study was similar to many others; cancer cells were grown in a laboratory, exposed to the ‘natural’ ingredient, and the degree to which growth was slowed down or that cancer cells were inspired to drop dead was measured. In this particular experiment, chronic lymphocytic leukemia B cells were the targets. Nothing unique about this setup.

And no surprise that the curcumin was found potentially useful. Here let me quote from the results in the abstract and then translate the interesting parts:

“Curcumin induced apoptosis in CLL B cells in a dose-dependent (5-20 micromol/L) manner ...”

‘Apoptosis’ is when a cell decides life isn’t worth living and self-destructs. Curcumin convinces these leukemia cells to commit suicide. The more curcumin added to the cells, the more died.

“Coculture of CLL B cells with stromal cells … decreased sensitivity to curcumin.”

Adding some other cells, stromal cells, into the mix decreased the curcumin effect; fewer cancer cells died.

“When curcumin was administered simultaneously with EGCG [green tea], antagonism was observed for most patient samples.”

Adding green tea extracts along with curcumin to the mix of leukemia and stromal cells caused, what these scientists called ‘antagonism.’ That’s an odd term and you need to view the full text article to get an idea of what they mean by antagonism. Put simply, the combination of the two natural substances, green tea and curcumin, didn’t work as well as predicted: “… simultaneous culture had a less than additive effect.” That is if you measure the anti-cancer effect of each substance separately, you can add the two ‘effects’ together to predict what should happen when both are used simultaneously. It turns out they don’t work as well as predicted; they antagonize each other.

“In contrast, sequential administration of these agents led to substantial increases in CLL B-cell death ...”

When instead of adding both curcumin and green tea to the culture at the same time, the cells are instead exposed to one agent and then the other, the story changes completely. They tried treating the cells first with curcumin followed by green tea, and vice versa. To quote the authors, “… sequential administration led to dramatically more leukemic cell death than simultaneous administration.”

Not only did exposing the cancer cells to these substances one at a time matter, but order mattered as well. Green tea first, followed by curcumin, worked much better than if the cells were exposed to curcumin first.

Think about the implications this brings to our practices. Sequential administration of treatments may work better than simultaneous treatments. Order matters. In this case green tea works better first.

Typically in practice we pile a bunch of different substances into a patient’s blood stream on the assumption that each has a specific action and these effects will add together. This reminds me of those combination locks that have four or five parallel numbered rings and to open the lock. You line up a number on each ring, get all the right numbers in a row at the same time, and the lock opens.

This leukemia study makes that image obsolete. If sequence matters, just knowing the combination is no longer enough. This is more like the dial lock on a safe. Sequence is essential. Three turns to the left and stop on the right number, then turn the dial to the right past your first number and stop on another specific number. And so on…

Think about this: our cancer patients often take a long list of supplements. This study suggests that, at least in chronic lymphocytic leukemia, we should start them on green tea for a period of time and then switch to curcumin. What if it is a similar story with quercetin, resveratrol, sulforaphane, vitamin D, melatonin and so on? What if there is a ‘best sequence’ for all of these? What if that combination were to vary by cancer? By patient? Or even by dose?

This is worth stewing about. It makes me think of certain patients who tell me they vary what supplements they take day-to-day based the way a pendulum held in their hand swings. Though this sounds less than ideal, it can’t work any worse than flipping a coin to decide on a sequence, which for the time being may still be of some utility.

Now that this study has been published, we shouldn’t be surprised to see other studies up asking this question: “If order matters, what comes first?”

Ghosh AK, Kay NE, Secreto CR, Shanafelt TD. Curcumin inhibits prosurvival pathways in chronic lymphocytic leukemia B cells and may overcome their stromal protection in combination with EGCG. Clin Cancer Res. 2009 Feb 15;15(4):1250-8.

Two Schools

By Jacob Schor, ND, FABNO

Curcumin is the principal curcuminoid of the popular Indian spice turmeric, pictured above.
Photo by FootosVanRobin via Flickr, used under the Creative Commons License.

There were two distinct schools of thought regarding the dosing of herbal medicines when I was a student at National College of Naturopathic Medicine during the 1980s, a couple of decades ago. Most of our teachers in Portland thought in terms of what I now regard as low doses of botanical medicines. We would often prescribe doses of just several drops of tincture diluted in water.

Apparently those at Bastyr University held a different view. This was brought home when Dr. Silena Heron came down to Portland from Seattle one rainy day and lectured our class. She didn’t talk of drops but instead talked of doses in milliliters and teaspoons. She was dosing herbs to get pharmacological effect while we were looking for homeopathic effects.

These thoughts are on my mind because of a study I came across recently about curcumin and cholesterol. Over the years a number of papers have looked to see if curcumin or turmeric lowered cholesterol. Some report benefit, others not. But this paper reports something I would have not predicted. Let me tell you more about it.

The paper, authored by Alwi et al., was published in 2008 in an Indonesian medical journal and looked at the effect of curcumin on lipid levels in patients with acute coronary syndrome. This is a broad term, referring to most any situation in which the heart isn’t getting enough oxygen. For a year, between May 2005 and May 2006, the researchers enlisted patients at several hospitals to participate in a randomized double blind controlled trial. They administered curcumin in escalating doses that ranged from a low dose of just 15 mg/ 3 times per day, up to 60 mg/ three times a day, on the participathing patients’ lipid profiles. The researchers tracked total cholesterol, LDL, HDL, and triglycerides along with other common blood parameters in 63 patients who completed the study.

The researchers report that they saw lipid improvements stemming from the curcumin that varied with the doses and that in regard to, “… the effects of curcumin on total cholesterol level and LDL cholesterol level, there was a trend that the lower the dose of curcumin, the higher the effect of reduction. For HDL cholesterol level, there was also a trend that the lower the dose of curcumin, the higher the effect of increase in HDL cholesterol level.”

Let me make sure you are reading this right. They are telling us that 45 mg of curcumin per day worked better than 180 mg per day. Neither of these are particularly high doses. The smallest capsule we have on our pharmacy shelf contains 250 mg of curcumin and that product in particular claims enhanced absorption so that it is equivalent to a dose of 2,000 mg. Our standard curcumin product comes in 750 mg capsules. If we believe this Alwi study, we should divide those 750 mg capsules and spread it out over a two week period.

Perhaps we need to rethink our ‘more is better’ assumptions and even re-examine our earlier habits of using tiny doses when it comes to prescribing some botanical medicines.

The late William Mitchell would sometimes use a specific word to describe how a botanical extract affects an organism. He would say that it “informs” the body or the mind or the vital force. I don’t pretend to understand exactly what Dr. Mitchell meant by the word ‘inform,’ but I’ve taken it to mean that the particular molecules isolated from the plant bring information, that teaches or shows by example, a different pattern of behavior and function to the organism. Thus botanical medicine can act as a catalyst to change function.

We certainly have some unpleasant examples with which we might illustrate this idea. Certain addictive drugs appear to trigger permanent changes in brain chemistry after even a single exposure. Even if we aren’t talking about crack cocaine, it is not unreasonable to think that other more benign plant extracts will also cause lasting permanent changes in function. Botanical medicine, when well practiced, is perhaps more like the automatic software updates that my computer routinely downloads. They teach the system how to work better and update it so it understands how to respond to new challenges.

If we are using the analogy that herbs act like catalysts, then it makes sense that relatively small doses are all that’s needed to turn the trick. Maybe we only need the large doses when we are using herbs as drugs and not as information carriers. Perhaps drugs deliver orders to the body, while herbs deliver knowledge. [If I keep up this kind of train of thought I may have to move back to Oregon and eat granola again.]

These are the sorts of discussions we engaged in decades ago as naturopathic students. We hear these kinds of arguments less often these days. I often just reach for standardized plant extracts whose chemical actions have been multiplied by refining, distillation and concentration. More is better and stronger is better; these have become our quiet mantras. We once condescendingly attributed this type of thinking to medical doctors (especially those claiming to practice natural medicine) and considered it to be an inferior approach to treating the patient. We allowed that some one in our profession might out of necessity fall back and prescribe botanical medicine like this out of desperation but it wasn’t the preferred path of treatment, the way a real naturopathic doctor worked. We were such idealists.

Luckily many of us still are idealists and this paper on curcumin should serve as a reminder. Sometimes less is more. Sometimes what we need is a tiny nudge from something so small as to seem like magic. Or perhaps, in our rush to keep up with all the new science, we have to leave a little space in our understanding for the magic in our medicine to do its work.