Can this ancient, hidebound system survive the scrutiny of modern medicine?

Five hundred and twenty-three. That is the number of research papers and studies on the herb Ashwagandha in the online database of medical literature known as Pubmed.

If papers outside Pubmed are included, the number may run into over a thousand. The range of medical conditions for which Ashwagandha is being investigated today is dazzling—among them cancer, protection against chemotherapy, memory impairment, skin pigmentation, stress, sore throat, depression, tooth decay, tuberculosis and hormonal disorders.

Several of these studies conclude with positive findings, leaving ellipses of expectations.

Zero. The number of Ashwagandha-based drugs a practitioner of modern medicine can prescribe.

This dramatic statistic summarises the paradoxical state of Ayurvedic drugs in the medical world today. Reams upon reams of research exists, much of it dramatic and worded most optimistically, but they are not taken seriously by modern medicine. Herbal extracts of Ashwagandha proliferate in the market, but no self-respecting psychiatrist would prescribe any of them for anxiety, one of the claimed indications for Ashwagandha. Thousands of other herbs and formulations are in similar stasis—they enjoy immense popularity and a Rs 8,000 crore market among Indians, but modern medicine rejects many of them. To put it another way, Ayurvedic medicines have barely got their foot in the door of mainstream modern medicine, and to many researchers in the field, this situation is a colossal disappointment.

Why hasn’t the dazzling array of research into Ayurveda resulted in proven drugs? Why are these drugs incomparable to modern medicine? Is it that Ayurveda works on faith alone? If so, what is one to make of the thousands of ‘scientific’ studies arguing for Ayurvedic drugs?

THE MIRAGE OF AMPLE DATA

To understand the problem, it helps to first understand the scale of effort and investment necessary to develop a single new modern drug. It takes 15-20 years of research and $1-2 billion to bring a drug to market. Even after this, there is no guaranteed outcome. After ten years of drug development, a drug may enter the late stage of testing, known as phase 3 trials, and fail to prove its efficacy. (See ‘What it takes to develop a drug’, Page 23).

This approach needs focus. And research into Ayurvedic drugs has been anything but focused. Unlike in the case of a synthetic drug developed by a pharmaceutical firm, where all clinical research protocol is adhered to strictly, chaos reigns in the Ayurvedic drug sector. “Somebody is doing studies in rats, somebody is doing it in mice, somebody is doing it in guinea pigs. They are all publishing data, but you cannot take it all together as a whole,” says K Nagarajan, who headed the medicinal chemistry department at Ciba-Geigy’s (now Novartis) Indian R&D centre in the 1970s and 80s.

To take the example of Ashwagandha alone, there exists no ‘single definitive trial,’ according to Keiran Cooley, a Canadian naturopath who carried out a clinical study in 2009 using naturopathic interventions, including Ashwagandha, in patients of anxiety. “The state of evidence on Withania (Ashwagandha) is one of complexities—there are both positive and non-positive studies across a wide variety of disorders… there are promising findings, but… evidence isn’t convincing enough in any one area,” says Cooley.

If some research findings are too disconnected and conflicting, other research is of poor quality. For example, the studies that appear on the website of India’s apex body for promoting Ayurveda, the Central Council for Research into Ayurvedic Sciences, do not adhere to the gold standard of modern research—the placebo-controlled clinical trial. Nor do they follow the best protocols, says Nityaanand, the erstwhile director of the Central Drug Research Institute (CDRI), which developed Guggulipid—India’s first modern drug from an Ayurvedic lead—during his tenure. Such research is, therefore, irrelevant to a drug developer.

Finally, a whole set of clinical data out there is outright fraudulent. Firms that sell over-the-counter Ayurvedic drugs can buy positive research results for a price, says Sanyasi Kalidindi, the founder of US-based Ayurvedic drug research firm Natreon.

In other words, the wealth of data that exists on many Ayurvedic drugs is a mirage.

CLASH OF OPINIONS

Why is there so much bad research in Ayurveda? Like the seven blind men and the elephant in the Indian parable, every scientist has a different perspective.

One set of scientists argues that a rabid nationalistic fervour for everything Indian has made Ayurvedic practitioners regard the classical texts as the last word, insisting that modern scientific endorsement is not important for them. Also, the jingoistic zeal has led to looser regulations for Ayurveda, which has seriously harmed the credibility of this ancient form of medicine. Ram Vishwakarma, who heads the Indian Institute of Integrative Medicine in Jammu, a CSIR (Council of Scientific and Industrial Research) laboratory that researches herbs for drug development, says, “The challenges (in developing drugs from Ayurveda) are many, but the biggest is the arrogance of many people who practise Ayurveda.”

Another set of scientists points the finger the other way, claiming it is Western science that is arrogant and has not tried hard enough to accommodate Ayurveda.

According to Ashok Vaidya, who heads research at ICMR’s (Indian Council of Medical Research) Advanced Centre for Reverse Pharmacology, “Western science identifies these systems as folklore. They don’t see it as an organised system of knowledge—this is an alien epistemology to them because their medical traditions only go as far back as the medieval times and renaissance.”

There is also the very real problem of complexity in natural-product research. It is harder to develop a drug from Ayurveda than it is to build a synthetic molecule, because of the large number of compounds in each Ayurvedic herb. All these factors are responsible for the state of Ayurvedic medicine today.

CAN TOO MUCH FAITH BE A PROBLEM?

One of the reasons why research into Ayurveda is so underdeveloped is that there has always been an alternative—the herbal route.

The Drug Controller General of India (DCGI) allows firms to manufacture and sell Ayurvedic medicines as long as they are described in the ancient texts. Unlike modern drugs, DCGI does not require Ayurvedic medicines to show clinical-trial data proving they are safe and effective. The logic of this sanction is that centuries of use has already made the case for these medicines. The law has allowed a market for herbal medicines to flourish, promoting firms like The Himalaya Drug Company and Dabur. But on the downside, the thousands of formulations being sold in the market have never undergone modern scientific testing. Whether these tests would validate the claims made by the ancient texts is anybody’s guess.

An interesting case study is Himalaya’s Liv.52, one of the big commercial success stories in Ayurvedic medicine. This liver tonic is a combination of six herbs and a bhasma, a preparation in which a metal (iron in this case) is treated according to a process defined in Ayurvedic texts.

Liv.52 today has a 47 per cent market share in liver drugs in India, garnering annual revenue of Rs 167 crore. Such a market share would not be attainable if consumers of modern medicine were not also taking Liv.52. Indeed, according to Pralhad Patki, Himalaya’s head of research, many allopathic doctors prescribe it.

Scratch the surface, and a more complex picture emerges.

Three of the gastroenterologists (who typically treat liver diseases) I spoke to for this story said they would never prescribe Liv.52, except as a placebo. This is what they said: liver disease or hepatitis is typically of two kinds—induced by a virus or having other causes, as in the case of alcoholic liver disease or fatty liver disease. Except in chronic cases, the virus causing hepatitis is usually self-limiting, meaning the patient’s body fights it away and a spontaneous recovery occurs in a couple of months in 99 per cent of cases.

No treatment is needed here, unless symptoms such as nausea or fever develop, in which case, the doctor prescribes drugs for these symptoms. Yet, patients become impatient and ‘seek instantaneous relief,’ says Dr Umesh Jalihal, head of the department of gastroenterology at MS Ramaiah Memorial Hospital in Bangalore. “So we prescribe liver tonics.” According to Jalihal, tonics such as Liv.52 have no proven action. They are merely given to placate the patient. When chronic liver disease does occur, specific antivirals such as Interferon or Ribavarin are called for.

Among the three practitioners of modern medicine mentioned above, the concern was the same—Liv.52 does not have enough clinical trials supporting its efficacy. Nor is it known how it will interact with modern drugs for liver disease. And this information is critical.

Ironically, The Himalaya Drug Company is known as one of the few Ayurvedic drug firms in India that undertakes clinical research. Patki says Liv.52 has more than 250 clinical trials supporting it. Why isn’t all this research enough?

Let’s take the example of Himalaya’s 51-patient clinical trial on Liv.52HB (a more potent variant of Liv.52 that claims to cure hepatitis B), which was published in the reputed Dutch journal, Antiviral Research. This study found that the drug was able to clear the virus effectively in patients of chronic liver disease.

Despite the impeccable reputation of the journal it was published in, the study comes with a few caveats. It notes that larger trials are needed to confirm results. Secondly, this trial does not compare the medicine with a placebo. As a modern drug, the Liv.52 HB trial would qualify as merely an early-stage study—promising but not definitive (See ‘What it takes…’). “Frankly, a large part of Himalaya’s research is only aimed at marketing its drugs,” says Vaidya. Compare clinical data on Liv.52 HB with that on Interferon—a modern drug for hepatitis B. It is supported by hundreds of trials, conducted in various countries and published in peer-reviewed journals. In terms of the sheer scrutiny it has been put through, it beats Liv.52 HB hands down.

To be fair, Himalaya’s Liv.52 and Liv.52 HB are among the better herbal drugs in a highly unregulated market, because firms such as Himalaya and Dabur use standardisation and quality control techniques to ensure the presence of the medicine’s active chemicals. The key question is: do these herbal drugs offer the same proof of efficacy that modern drugs do? The answer is no. To claim a cure for hepatitis, a modern drug would require more data than Himalaya currently provides for Liv.52 HB.

But is it even possible for Ayurveda-based drugs to meet the requirements of modern medicine?

PROMISING PRECEDENTS

Seventy per cent of all modern drugs today come from natural sources. This means there is enough precedent for drugs being developed from herbs. Quinine, the frontline treatment for malaria in the 1940s, was first isolated from the bark of the Cinchona tree in 1820 by two French researchers. Also, Ayurvedic herbs have yielded modern drugs too. A remarkable success story is that of the blood-pressure lowering drug Reserpine, which was isolated from Rauwolfia Serpentina or the Indian snakeroot by Ciba-Geigy scientists in the 1950s. Sage Charaka had documented the snakeroot or Sarpagandha in his very ancient text, Charaka Samhita.

This drug was also the first to be shown to have anti-depressant effects in a clinical trial, leading to ‘a watershed in the development of anti-depressants,’ according to Ashok Vaidya, in a 2009 paper on drug discovery from traditional medicine. Reserpine had harsh side effects and was eventually replaced by better blood-pressure drugs, but it is still in occasional use.

Cancer drugs Vinblastine and Vincristine come from a flowering plant used in Ayurveda. While these drugs were developed outside India, scientists from the Central Drug Research Institute, an Indian government organisation, developed cholesterol-lowering drug Guggulipid from the herb Guggul in 1986.

What this handful of examples proves is that ancient Ayurvedic doctors had put together a virtual treasure trove of medicines thousands of years ago without access to modern scientific methods. The bigger conclusion, however, is that Ayurvedic sources can yield modern drugs. Why then are there so few such drugs?

BIAS AGAINST TRADITIONAL MEDICINE?

To understand the bias that scientists such as Vaidya talk about, the process of developing Ayurveda-based drugs needs some elucidation. These drugs can be developed along two distinct routes. In the first, the active ingredient (alternatively referred to as ‘pure compound’ or ‘single molecule’ in this story) is isolated from a herb. This is what Ciba-Geigy scientists did when they isolated Reserpine from Charaka’s Sarpagandha. It is also what scientists at the Central Drug Research Institute did when they isolated Guggulipid from the Guggul herb during Nityaanand’s tenure. The second way is to use herbal extracts—the Liv.52 way. Either you have a combination of extracts from several herbs, as in the case of Liv.52, or an extract from a single herb, as in the case of Piramal Enterprises’ Tinefcon ointment for psoriasis.

The second route has little precedent of acceptance as a drug in modern medicine. Such medicines tend to go the dietary-supplement route, which means modern medicine practitioners cannot prescribe them.

Till 2004, the US Food and Drug Administration (FDA) did not have guidelines for testing herbal extracts as drugs, making it impossible for herbals to meet the same stringent regulatory requirements that synthetic drugs needed to clear. After the FDA made its requirements more herb-friendly in 2004, only one herbal drug—a green-tea extract called Veregen for treating genital warts—has been approved in the US.

The FDA’s stance reflects the stance of much of modern medicine—that traditional medicines should prove their efficacy the same way modern drugs too.

This is difficult.

For one thing, all modern medicine hinges on the concept of the pure compound. Which herbs are not.

Says Nagarajan, “When you go to the US or European or Indian pharmacopeia, you will find that these drugs are very often more than 99 per cent pure, often more than 99.5 per cent pure; often at least 99.8 per cent pure. Single impurities are almost always expected to be 0.1 per cent or less.” This purity allows for consistency. Each time you synthesise a pure compound, you can be sure it is the same drug, with the same predictable effects.

Ayurvedic medicines, on the other hand, contain herbs—mixtures of several compounds. The medicine itself, such as Chyawanprash, is a mixture of several herbs, increasing complexity by an order of magnitude. This makes it tough to get consistency across multiple batches of production.

Moreover, Ayurvedic drugs rely on the concept of synergy, which means single compounds may not work well enough alone. One compound may be complementing another, playing Robin to its Batman. The best proven example of synergy is Trikatu—a mix of three peppers prescribed to improve digestion in Ayurveda. It has now been discovered that piperine, the active compound in pepper, enhances the effect of certain other drugs. Taken with piperine, these drugs can be administered in smaller doses for the same effect.

Such unorthodox mechanisms of action made Ayurvedic drugs opaque to modern medicine for a long time. Today, though, the FDA does not require a single active ingredient to be isolated from a herb for it to become a drug.

While this is great news, India evidently has not taken them up on the offer. Traditional Chinese Medicine preparations outnumber Indian preparations in the herbal drug applications with the FDA. In 2010, Dansheng Dripping Pill, a traditional Chinese medicine, became the first herbal drug since Veregen to enter Phase 3 clinical trials. No Ayurvedic drug has come this far.

A modern drug typically goes through this drug-testing process before it is launched. After tests in animals, phase 1 trials are carried out in humans to test for safety. In Phase 2, the drug’s claimed effects are tested. Phase 3 compares the drug with the current standard treatment or a placebo.

Comparing the drug with a placebo is important because many patients recover from illnesses without any treatment. A drug developer must prove that it is the drug that caused the cure and not the body’s own recovery mechanism. Plus, the drug must show that it is at least as effective as the standard treatment already in use.

THE CHALLENGE OF COMPLEXITY

What about the single compound route? It turns out that even though modern science accepts such drugs, the challenges are no less formidable. Developing a single-compound drug from Ayurveda is a bit like finding a needle in a haystack. More accurately, it is like finding a needle in many haystacks, because a drug maker is trying to find this compound in a mixture of many herbs.

The first hurdle is that any Ayurvedic herb comes in several varieties—some of high quality and some of little use. “The amount of active ingredient is practically nil in the Guggul grown in Kerala, while it is very high in the Guggul grown in Afghanistan,” says Nityaanand. Second, the herb that grows in summer is different from the one that grows in winter, which is different from the one that grows in monsoon. Third, it is possible that the herbs available millenniums ago, when the ancient Ayurvedic texts were written, do not even exist anymore or have mutated.

Therefore, collecting the right plant in the right season is itself a challenge. Next, it must be standardised, which means ensuring the presence of the active compounds in it.

Many of the extracts you buy in the market may not meet these quality standards. “When you buy crude plant powder from the market that is labelled ‘Brahmi’, you don’t know what Brahmi it is,” says Nagarajan. It is only when the right herbs have been found after crossing these many impediments that the drug developer begins to look for the needle—the compound in the herb that really works. To get to Guggulipid, CDRI scientists had to pare away several other compounds that were merely co-passengers on the bus. And the process took them 30 years, says Nityaanand.

Finally, natural molecules are tougher to build in the lab. For many such drugs, their makers have had to rely on the availability of the actual plant through agriculture. The price of the antimalarial Artemisinin, which is widely used to treat malaria in Sub-Saharan countries, fluctuated wildly in the 2000s due to short supply.

Meanwhile, synthetic ways to make Artemisinin gave low yields, making them a poor alternative.

HOW TO DISCOURAGE GOOD RESEARCH

Given the difficulties of developing Ayurvedic drugs, their best hope is the interest of large pharmaceutical firms with the competence and funds to develop them. But according to Ram Vishwakarma, many steps taken by the Indian government have repelled such interest.

One such step was the National Biodiversity Act that India introduced in 2002. This act restricts access to Indian plants for research and drug development, leaving pharmaceutical firms in India and abroad up in arms about it. “It is the most draconian and bureaucratic piece of legislation,” says Prashant Reddy, an intellectual property lawyer, who blogs regularly on the IP issue website, Spicy IP. “It can throw scientists into jail for not securing permission from the National Biodiversity Authority (a body instituted under the Act) before accessing biological resources in the country. The NBA can also impose and collect some kind of fee or tax for the use of the nation’s biological resources. All of this just makes it extremely difficult for companies to conduct research in anything in the traditional knowledge field.”

Apart from being a deterrent, this law is difficult to interpret. “It is so complicated, so difficult to follow. We are struggling to find out whether we are conforming with the law,” says Swati Piramal, the vice-chairperson of Piramal Enterprises, one of the few Indian firms researching traditional-medicine leads for new drugs.

While creating such complicated deterrents to drug research, India has not created any incentives. “You can make laws saying don’t do this and don’t do that, but the industry needs guidance and encouragement too, right?” says Piramal.

In 2003, India did make an attempt in this direction with an ambitious programme to foster innovation. It was called the National Millennium Indian Technology Leadership Initiative, under which several grants were given to research organisations to develop herbal drugs. As of 2013, however, no drug from this programme is in the market. They have all hit roadblocks either during research or before being launched in the market. A herbal psoriasis drug by Lupin was said to be in Phase 2B clinical trials in 2009, after which there has been no news of it. At least four other drugs developed for conditions ranging from diabetes to arthritis by a network of Indian research organisations and hospitals reached late stage trials. But negotiations between CSIR and drug developers to commercialise these drugs have made little leeway, says Bhushan Patwardhan, who steered several of the Millennium Initiative’s herbal drug-development programmes.

In the words of Goverdhan Mehta, a member of the Scientific Advisory Council to India’s Prime Minister, such government efforts in Ayurveda are always ‘bits and pieces’ research, not necessarily involving competent people and the industry. “Most of the engagements I have witnessed over the years have all been superficial and goody-goody. The industry will not become involved unless they think it’s worthwhile for them,” he says.

In sharp contrast, China has made major strides in promoting Traditional Chinese Medicine (TCM) research, despite being up against the same problems. Their approach has been a concerted one, driven by the government.

According to Ikhlas Khan, who heads the Mississippi-based Centre for Research into Indian Systems of Medicine (CRISM) that collaborates with US regulatory bodies to promote scientific acceptance of Indian medicine, “Modernisation of TCM is a national priority in China and is backed by financial support from [their] Government. There is a tremendous amount of research being done in China and in collaboration with Western countries to generate scientific evidence and revalidate the system.”

In March 2008, the US Pharmacopeial Convention, a non-profit American body that works with the government, entered an agreement with the Chinese Pharmacopoeia Commission to improve the quality of traditional Chinese medicine. While this applies mostly to supplements, such attempts at standardising quality can only help TCM. Meanwhile, a government-backed industry-university alliance was launched recently, including two universities and 12 drug firms. TCM research papers being published every year far outnumber those on Ayurveda. Patwardhan cites a telling statistic: “If you search the SCOPUS database (an online database of academic publications) for papers on Ayurveda, you will see maybe 1,300 papers. If you look for TCM, you will see something like 15,000.”

Scientists agree that China’s brute-force approach is what India needs too. Comparing China’s effort with programmes driven by the Indian government, Vishwakar- ma says our approach is simply not widespread enough. “You need scale in something like this. We should be doing 500 trials at a time, not one or two,” he argues, reasoning that the failure rate is high for clinical trials.

In 2009, Chinese Universities developed a natural extract database in collaboration with Harvard University, which painstakingly adheres to high standards of quality for herbs, explicitly to resolve the problem of variability in herb samples for clinical trials. “Such an integrated approach has always been missing in India,” says Arvind Saklani, assistant director, natural products botany at Piramal Enterprises.

“My belief is that the Chinese will discover drugs from Ayurvedic plants before we do,” concludes Vishwakarma. “Whatever herbs are available on this side of the Himalayas are also available on the other… and what they are doing is the exact opposite of what we are.”