Dr Paul Clayton, Medical Pharmacologist, Former President of the Forum on Food and Health at the Royal Society of Medicine

My life in nutritional science

My science


There are better, more effective, natural ways to deal with Arthritis than Big Pharma’s magic bullets, with all their possible side-effects.

The enquiring reader may wonder – if the combination I recommend can help to re-build joint tissue and bone, should it not help with osteoporosis? I believe it may.


Pain is a problem that affects many. As one of the most common symptoms of most diseases, it afflicts us all at different times and with differing degrees of intensity.

As a result, a great deal of the history of medicine centres around the search for effective methods of pain relief – particularly joint pain. This is reported by a staggering 13 million people in the UK, according to a MORI poll conducted by the Arthritis Research Campaign.

A key cause of pain is inflammation, which is why the search for effective anti-inflammatory agents has been so intense. They go by the generic name of NSAIDs (Non-Steroidal Anti-Inflammatory Drugs).

Aspirin (originally created by Bayer and derived from the plant meadowsweet) was the first commercially significant NSAID. In 1966 Stuart Adams, a scientist working for Boots the Chemist, developed ibuprofen. Ibuprofen is more powerful than aspirin and significantly less likely to cause stomach irritation.

It had been discovered in the ‘70s that aspirin and the other NSAIDs all work by inhibiting an enzyme in the body called cyclooxygenase (COX). COX facilitates the body’s ability to synthesise prostaglandins, hormone-like compounds that are involved in tissue damage, inflammation and pain.

To understand how the pain of arthritis is caused, how that pain can be stopped and how the underlying cause can be dealt with, you need to understand the following process. Don’t worry too much about the scientific terms, it’s only important that you follow the logic!

1. When tissue cells are damaged – for example by arthritis – not only is inflammation created, but an enzyme is released called PLA (phospholipase).

2. The PLA enzyme breaks down the outer membrane, not only of the damaged cell, but of neighbouring cells. These cell walls are made of fatty acids called phospholipids – which then break free.

3. The broken-down fatty acids are then processed by three further enzymes called COX 1, COX 2 and LIPOX 5. The end result of the process is the creation of another fatty acid called a prostaglandin.

4. In turn prostaglandins create pain – which is recognised by pain receptors and transmitted to the brain.

5. Prostaglandins also make the original inflammation worse which creates a vicious circle – because more PLA is created and therefore more cell membranes breakdown, and therefore more phospholipids are released and therefore more prostaglandin is produced, etc, etc.

NSAIDs work by preventing the broken down phospholipids from reaching COX1 or COX2 – which is why they are called COX Inhibitors. But they can’t block the pathway to LIPOX. And they only affect the symptoms – the pain – they do not address the cause.

The main problem with NSAIDs is that they have a tendency to cause gastric ulceration. This is estimated to affect as many as 20% of long-term NSAID users – and each year several thousand of these result in death.

So scientists began to look for better NSAIDs and in the ‘70s found there were two forms of COX, designated COX-1 and COX-2. It became apparent that COX-1 inhibition was the cause of the ulceration problem, and drug companies therefore began to search for compounds that blocked COX-2 without affecting COX-1.

This more specific approach, it was hoped, would produce a safer analgesic. It eventually produced the COX-2 inhibitors like Celebrex , Vioxx and Bextra.

These drugs were, to begin with, huge commercial successes; but this prime example of Big Pharma’s obsession with searching for a magic bullet led to what David Graham (then the associate director for science and medicine at the US FDA’s Office of Drug Safety) described in 2004 as “maybe the single greatest drug-safety catastrophe in the history of the world”.

He believes, on the evidence made available to him, that the COX-2 inhibitor Vioxx may have caused as many as 139,000 heart attacks, strokes and deaths. But although Vioxx made all the headlines, it was only the first of the lucrative COX-2 inhibitors to be linked to an increased risk of cardiovascular problems.

It seemed that whole class of COX-2 inhibitors carried this danger, to a greater or lesser extent. The UK NHS guidance web site for doctors states baldly: ‘NSAIDs may worsen asthma, hypertension, renal impairment, or heart failure.’

Even ibuprofen, the familiar painkiller sold over the counter for anything from arthritis to hangovers, and which has some effect on COX-2, was dragged in. Research in the British Medical Journal (Hippisley-Cox ’05) showed that patients prescribed ibuprofen are almost a quarter more likely to have a heart attack within three months than those who do not take the drug.

Why? Because COX-2 inhibitors reduce prostacyclin (a fat molecule), and prostacyclin controls the way in which blood vessels adapt to stresses such as high blood pressure.

By reducing levels of prostacyclin the COX-2 inhibitors not only contribute to an increase in blood pressure, but also accelerate the process of atherosclerosis (furring of the arteries), interfere with key healing mechanisms, and possibly increase the risk of blood clots.

This combination of effects, the researchers suggested, could all interact to increase the risk of heart attack and stroke even in previously healthy individuals.

Former Vioxx users and their survivors are filing thousands of liability suits against Merck based on those allegations, and the apparent fact that early negative trial results may have been suppressed. If the Vioxx plaintiffs win their cases the legal payouts are currently estimated at between $10 and $15 billion.

The Natural Nutritional Alternative

Whatever the rights and wrongs of the pharmaceutical industry, the fact remains that there were – and are – a number of natural compounds derived from foods and herbs which are effective and safe anti-inflammatory agents.

The best documented of these is the food spice turmeric, which has a long history of use in Ayurvedic medicine in the treatment of painful conditions from sore throats to arthritis (Scartezzini & Speroni 2000).

Long ignored by the drug companies, many leading scientists have nonetheless researched this spice and its active constituents, called curcuminoids, in both animal and human studies. The results are clear: curcuminoids are both highly effective and safe. Both turmeric powder and oleoresin are on the US FDA list of substances Generally Recognized As Safe (GRAS).

In the light of the COX-2 scandal it is particularly interesting to note that not only do curcuminoids NOT cause any increase in the risk of heart disease, they actively protect against it. For good measure, there is convincing evidence that they may well protect against cancer and Alzheimer’s also. (See references and my articles on heart disease, cancer and Alzheimer’s.)

This might seem to be too good to be true, but the curcuminoids are just one example of a wider category of phytonutrients called flavonoids, a family of compounds which occur in many plant foods such as berry fruits and which are associated with better health prospects.

Because of dietary changes we no longer eat nearly enough of these compounds, and suffer ill health as a consequence. Taking curcuminoids and other flavonoids and including foods that contain them merely restores our diet to an earlier, more natural and healthier state.

The flavonoids have always been a key element in our diet, and our bodies have over the millennia learned how to use them in many different but complementary ways. In complete contrast to the ultra-specific ‘magic bullet’ drugs developed by Big Pharma, the flavonoids act at many different sites in the body, modifying and improving many of our physiological systems in a highly coordinated manner.

How do curcuminoids work?

Remember how NSAIDs work? By blocking broken-down phospholipids from reaching COX and COX-2. Well, curcuminoid works in exactly the same way – it too acts as a COX-2 inhibitor – but it also blocks the pathway to LIPOX, and it is a very potent anti-inflammatory agent.

In other words curcuminoids act like the COX-2 drugs – but without the negative side effects.
So they are far more effective pain relievers.

Following the COX-2 tragedy, it is vitally important to ensure that new anti-inflammatory agents are not cardio-toxic. In the case of the curcuminoids, they are demonstrably not cardio-toxic. In fact, there is a good deal of evidence – see references – that they actually protect the cardiovascular system in a number of complementary ways.

1. They are powerful antioxidants.
2. They lower LDL (the ‘bad’) cholesterol, and protect it against oxidisation.
3. They damp inflammation in the blood vessel walls, reducing blood pressure and the tendency to form atheroma.
4. They prevent the excessive growth of smooth muscle cells in the artery walls. When these grow too thick, they begin to narrow the arteries and that can lead to higher blood pressure and potentially a blockage of the artery.

This is a powerful combination of cardio-protective effects. Indeed, many nutritionally minded clinicians already include turmeric and the curcuminoids in their cardio-protection programmes.

Gastro-protective – and perhaps cancer protective too

We cannot leave the curcuminoids behind without reference to gastric ulceration. Gastric ulcers are a common adverse effect of NSAIDs. Might curcuminoids do the same? No. In this case, the fact that the curcuminoids have many different actions in the body means that they actually protect against ulcers, and are used by some researchers as anti-ulcer and anti-dyspepsia treatments.

This is partly because the curcuminoids block a group of enzymes called Matrix Metallo-Proteases or MMPs which are actively involved in the process of ulceration AND in the process by which cancer cells spread. (See Cancer section.) Indeed curcuminoids are now being researched in cancer clinical trials.

Joint Management

So far we have only looked at curcuminoids as a means of pain relief. Now let us look in more detail at the conditions for which NSAIDs and COX-2 inhibitors are usually prescribed. The most important of these is musculo-skeletal pain, and joint pain in particular, which has two main causes: osteoarthritis and rheumatoid arthritis.

These two diseases are related, but sufficiently different that each disease requires a separate approach to treatment. 9 out of 10 arthritis sufferers have osteo-arthritis, most of the remainder have rheumatoid arthritis.

In osteo-arthritis, cartilage plates in the affected joints become thinner throughout a prolonged pre-clinical phase of attrition, until symptoms of joint pain and stiffness begin to emerge. The plates thin because the rate of cartilage loss (through wear and tear) is greater than the body’s ability to grow new cartilage; leading to a continuing net loss of tissue.

Normal And Arthritic Joint

The illustration on the left shows a normal healthy joint, the one on the right reveals osteo-arthritis. Excessive wear, outstripping repair, has resulted in the cartilage becoming rough and flaky and small pieces break off to form sharp loose fragments.

Weight bearing joints such as those in the neck, lower back, knees and hips are the most common sites of osteoarthritis.

We have seen that curcuminoids may be highly effective in damping down inflammation, and therefore pain, but they do not address the cause of that inflammation – which is excessive wearing of cartilage and bone at the joints.

Fortunately, there is persuasive evidence that with the right nutritional programming, damaged joints can effectively be re-built.

Glucosamine is now widely regarded as a safe alternative treatment for osteo-arthritis. Glucosamine supplements can increase the rate of cartilage growth, until it exceeds the rate of breakdown. As a result there is a continuing net increase in cartilage thickness, and the patient begins to ‘climb’, as it were, out of the symptomatic zone.

Glucosamine supplements, however, are not an ideal therapeutic intervention on their own. Glucosamine-induced cartilage regeneration is very slow; patients rarely experience significant benefits until at least the 3rd month. As a result, a sizeable number of patients give up before the healing effects can start to emerge.

In addition, the use of glucosamine sulphate (as opposed to the hydrochloride form) is problematic. It has been linked to a range of gastro-intestinal side effects, and is considered by leading experts to be associated with other, more serious problems. These include calcium loss and, in the 10% to 15% of the population whose micro-flora in the colon includes significant numbers of sulphate-reducing bacteria, an increased risk of colo-rectal cancer via the formation of highly toxic hydrogen sulphide.

Glucosamine hydrochloride avoids both these problems. Nor does it incur the sodium ‘loading’ associated with the glucosamine sulphate formulations, which can exacerbate blood pressure problems.

Vitamin K is also involved. Vitamin K is an essential element in the mineralization of bone. It is a necessary co-factor with glucosamine hydrochloride – and Vitamin D – in the re-building of bone.

The sequence then is this:

1. The natural anti-inflammatory effects of curcuminoids generally start to alleviate pain and inflammation in the affected joint(s) within a few hours of ingestion – which is what sufferers have come to expect of pharmaceutical products.

2. Over time, the curcuminoids’ anti-inflammatory (or anti-catabolic) effects begin to reduce the rates of tissue breakdown and thus tip the balance even further towards tissue regeneration, so that the cartilage plates grow more rapidly.

3. The combination of glucosamine hydrochloride, Vitamin K and Vitamin D will begin the process of regenerating both cartilage and bone.

What levels are needed? My ideal formula would include

1,400 mg a day of high potency Curcuminoids – at least a 90% extract.
(plus perhaps some pomegranate powder, which also has an
anti-inflammatory effect.)
1,200 mg a day of Glucosamine Hydrochloride
24 mcg a day of Vitamin D
150 mcg a day of Vitamin K

100 mg of Beta sitosterol

The reason for including Vitamin D and beta sitosterol is examined below.

Rheumatoid Arthritis

In rheumatoid arthritis the inflammation is driven by a different mechanism. The tissue damage is caused by auto-immune reaction – where the body’s immune system attacks itself.

In rheumatoid arthritis the inflammatory (catabolic) component is so strong that glucosamine alone is completely ineffective. Once the inflammatory fires have been safely ‘doused’, however, glucosamine hydrochloride can aid cartilage regeneration far more effectively.

The inflammation in rheumatoid arthritis is driven by a tissue-damaging auto-immune reaction, so in addition to using the anti-inflammatory curcuminoids, it makes excellent sense to damp down that part of the immune system that is doing the damage.

Beta sitosterol (derived from pine oil) and vitamin D do exactly this, and provide important immuno-enhancing side benefits. Both beta sitosterol and vitamin D compounds increase the ratio of TH1 (T-Helper 1) to TH2 cells and exert other profound anti-inflammatory effects.

This combination of actions has been shown to damp down the auto-immune mechanisms which drive diseases such as rheumatoid arthritis, Type 1 diabetes and, very probably, multiple sclerosis.

When dealing with rheumatoid arthritis, therefore, it is logical to combine Beta sitosterol, vitamin D and the curcuminoids to damp the damaging inflammatory reactions as effectively as possible.

Although beta sitosterol is not strictly necessary for the treatment of osteo-arthritis it is a powerful immuno-modulator and to have it in a joint relief formula means that both osteo and rheumatoid arthritis sufferers can take it. Rheumatoid arthritis sufferers also need to take extra vitamin D.

I say this because the level of Vitamin D that is needed to begin to damp down the auto-immune element in rheumatoid arthritis is, in my estimate, as high as 40 mg a day. This exceeds the officially agreed level for safe supplementation, so I would only recommend this is done under the supervision of a doctor.

There are better, more effective, natural ways to deal with Arthritis than Big Pharma’s magic bullets.

The enquiring reader may wonder – if the combination I recommend can help to re-build joint tissue and bone, should it not help with osteoporosis? I believe it may.