Stress

Dr Paul Clayton, Medical Pharmacologist

Former President of the Forum on Food and Health at the Royal Society of Medicine

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Stress

These are stressful times. According to our very own Health & Safety Executive, 5 million people in the UK alone feel very or extremely stressed by their work. This is 1 in 6 of the entire work-force. Not surprisingly, stress is thought to be responsible for about a fifth of all sick-leave.

Chronic stress genuinely makes people very ill. It makes you ill because it over-activates the brain resulting in the sustained release of adrenalin and cortisol into the circulation.

Short-term brain activation is fine, and is a crucial part of the fight-flight response. Over the long term, however, the resulting increases in blood pressure and platelet stickiness and the suppression of the immune system raise the risks of heart disease, stroke, infections, cancer, dementia and osteoporosis. A rather unpleasant catalogue!

Humans have always experienced stress, of course, and every culture has found ways of alleviating it. Some of these involve mental or spiritual techniques such as meditation, but most involve some sort of medication.

In the East, adaptogens like Ginseng have a long history of use (of which more later). In the West alcohol is the most common, but is equally a common cause of drunkenness and bad behaviour, alcoholism and liver damage. Worse, from the point of the view of the pharmaceutical industry, anyone can make the stuff – and there’s no profit in self-medication. But then along came the barbiturates …

Drug treatments – the awful side effects of addiction, overdose

By the 1960s and ’70s the barbiturates had became the treatment of choice for anxiety, insomnia, epilepsy and numerous other conditions. They were the wonder drugs of their time.

But it was not so long before the medical profession began to realise that these wonder-drugs were not as wonderful as they had thought. Barbiturate addiction was spiralling and barbiturate deaths were mounting, both from overdose and during the excruciating withdrawal syndrome.

Doctors wanted to treat their patients, but had become terribly aware they were harming as many people as they were helping. Thus, when the drug companies came to them with the next generation of wonder-drugs which would cure the barbiturate problems, they welcomed them with open arms.

These new wonder-drugs, which were safer and more effective than the barbiturates, were the benzodiazepines, or ‘benzos’.

Roche launched Valium globally in 1963. It was a huge success. By the time the Rolling Stones sang about ‘Mother’s Little Helper’ in 1966, Valium, Librium and the sleeping pill Mogadon had helped Roche to become the biggest pharmaceuticals company in the world. Valium’s triumph inspired every large pharmaceutical company to market a benzodiazepine of its own. Wyeth made a fortune with Ativan; Upjohn grew fat on Xanax.

But then the issue of addiction started to return. Patients on benzodiazepines were finding it extremely difficult to stop taking them. Symptoms of addiction were appearing in some cases as early as two weeks – and it was a vicious form of addiction. Patients addicted to heroin and benzos consistently said it was easier to come off heroin, despite its fearsome reputation.

According to the WHO, benzodiazepine addiction is now the second largest addiction after alcohol in the western world, with an estimated 1 million addicts in the UK alone! The problem is even greater in countries (India, South America and others) where benzodiazepines are available over the counter.

How, after the barbiturate disaster, could health care professionals have allowed this to happen?

Simple. The drug companies withheld information. They promoted benzodiazepines with inadequate warnings and exaggerated claims of their therapeutic value. They disseminated information on a differential basis according to the vigilance of the regulatory authorities in each country.

In the United Kingdom, they had it easy. All benzodiazepines on the market before the Medicines Act (1968) were automatically awarded “Licences of Right”. There was no assessment of safety or efficacy until the mid 1980s.

In the UK, drug information for prescribers is provided in the Data Sheets. Having obtained licences for their products as safe and non-addictive the drug companies were able to provide a correspondingly low level of safety information. The UK warnings were far lower than those required in North America, Scandinavia, or Australia. The UK Benzodiazepines Data Sheets were defective; manufacturers withheld safety information they were forced to publish in other, more stringent territories.

It is patently obvious that the drug companies concealed this vital information for financial gain. The fewer warnings in the Data Sheets, the happier doctors are to prescribe them. Benzodiazepines, with Valium at the head, became the biggest drug blockbusters of all time.

How do they work? How do they cause problems?

At the foot (bouton) of each brain cell or neuron (you have 100 BILLION of them!), there are several receptor sites. The job of neurotransmitters (which are chemical ‘facilitators’) is to enable electrical impulses that transmit thoughts and moods to jump from one neuron to another.

In times of over-stimulation, a neurotransmitter called GABA (gamma-aminobutyric acid) is released to tell the neurons to slow down or stop firing.

Benzodiazepines, eg. Valium, work by stimulating GABA receptors to amplify this calming effect ie. ramping up their activity. Since nearly half of all brain cells respond to GABA, GABA therefore has a general quietening influence on the whole brain.

There are three problems with the use of benzos: overdose, habituation and withdrawal.

Overdose
In overdose, which occurs particularly easily in the elderly, benzodiazepines cause over-sedation. Drowsiness, poor concentration, lack of coordination, muscle weakness, dizziness and mental confusion are all typical symptoms; they are strongly linked to an increased risk of work and traffic accidents, and falls in the elderly.

Memory loss, up to and including blackouts, is common. It is claimed that in some instances such memory lapses may be responsible for uncharacteristic behaviour such as shop-lifting. Long-term use is reported to lead to emotional blunting, and to trigger or exacerbate depression. Use during pregnancy can cause ‘floppy infant syndrome’, followed by withdrawal symptoms and possible developmental problems in later life.

Tolerance and dependence
Benzodiazepine users habituate ie. become tolerant to their drug. This means that the original dose of the medication has progressively less effect and higher doses are required to obtain the original effect. Doctors have often increased the dosage or added another benzodiazepine to keep their patients ‘happy’.

Tolerance to the sedative effects can appear within weeks. Tolerance to the anxiety damping effects develops over several months, and the drugs become increasingly ineffective. Long-term benzodiazepine use may even aggravate anxiety disorders. Many patients find that anxiety symptoms gradually increase over the years despite continuous benzodiazepine use, and panic attacks and agoraphobia may appear for the first time after years of chronic use.

Tolerance develops with most drugs of addiction. The body responds to the continued presence of the drug with a series of adjustments that tend to overcome the drug effects.

In the case of benzodiazepines, compensatory changes occur in the GABA receptors which become less responsive, so that the benzodiazepines become less and less effective.

At the same time there are changes in the secondary systems controlled by GABA, so that the activity of excitatory neurotransmitters, which was initially reduced, tends to be restored. Eventually even the number of receptors can be reduced and the patient’s ability to react positively to stress is permanently damaged.

Withdrawal symptoms
If the patient/addict now attempts to come off the drug, the combination of decreased GABA activity and increased excitatory activity leaves the brain in a state of unbalanced excitation. The patient is in the eye of an internal electrical storm, and develops anxiety symptoms, panic attacks, agoraphobia, insomnia, depression and a variety of physical symptoms.

Only a few manage to sail through this storm; the overwhelming majority head back to the shelter, however inadequate, of their prescription. Gradual dose-reduction schemes (‘tapering regimes’) are widely recommended by the medical profession, but have not been very successful (Ashton ’02 ).

Given all the above, it is truly astonishing that benzodiazepine prescriptions are still not being adequately controlled.

It is even more astonishing that the medical profession have not looked more closely at the range of natural products, both traditional and new, that are considerably safer alternatives, and act as effective but non-addictive anti-stress agents.

If ever there was a medical category where treating the cause naturally, rather than the symptom chemically, was called for, stress is it.

Natural Alternatives: Milk

Every mother knows that the best way to quieten a fretful baby is to put it on the breast. About 10 years ago a team of researchers at the University of Nancy began to wonder if something in the milk might be acting as a natural tranquilliser. They screened whole milk, and found very little.

They then digested samples of milk using the same digestive enzymes that a baby uses, which are somewhat different from adult digestive enzymes. They soon found that one of the peptides produced when milk protein (casein) was broken down in this way was a potent tranquilliser in test animals (Lanoir et al ’02, Messaoudi et al ’02) and in humans (Miclo et al ‘01).

This 10-amino-acid peptide is marketed as Lactium. Like l-theanine, discussed later in this chapter, Lactium is proving to be very popular; and as it is produced naturally from milk, even the obscurantists in Brussels have not been able to ban it. Weider is selling it in shakes at fitness stores throughout the EU and one UK company is developing a calming chocolate bar containing this same milk extract.

Lactium (and similar protein peptides from fish) work by inhibiting a neurotransmitter in the brain called Corticotropin Releasing Factor (CRF). CRF causes the pituitary gland to release corticotropin, which in turn stimulates the adrenals to produce the stress hormone cortisol (Bale & Vale ’04, Taché et al ’04).

Put simply, less CRF = less cortisol = less stress. And Lactium reduces the production of CRF. Clinical trials show that blood pressure response to stress and anxiety levels are reduced at a level of 150 mg a day.

Could you obtain the same benefits from drinking milk? Probably not. Since the effective dose of Lactium in humans is about 150 mg / day, and our adult digestive enzymes do not produce very much of the decapeptide, we would have to drink roughly 4 gallons of milk to obtain the same effect as taking a single Lactium-containing capsule or chocolate bar.

Tolerance, addiction and withdrawal issues do not occur with Lactium. Sedation and memory loss, two of the major problems associated with benzodiazepines, do not occur either.

Natural Alternatives: Tea

After milk, tea. People drink tea both to wake up and to relax. This might seem paradoxical but tea contains a stimulant and a tranquilliser. The stimulant is caffeine, and the tranquilliser is a rather less well-known compound, the amino acid l-theanine.

The combination of caffeine and l-theanine is an interesting one and has helped to make tea a big business, but there’s also good business in separating the two active constituents.

Various companies already extract the caffeine from tea or coffee and sell it in energy tablets and drinks. These help shelf-stackers stay awake in supermarkets and prevent drowsy drivers from dropping off at the wheel. Caffeine tablets are also an old favourite with students, who use them to stay awake for late-night cramming. New evidence, however, suggests that they might do better if they used l-theanine instead.

It was the Japanese-based Taiyo Kagaku company that pioneered the use of l-theanine. Billed as a natural tranquilliser, l-theanine’s main effect is to increase alpha waves in the brain (Kobayashi et al ’98, Sagesaka et al ’98, Kim et al ’01, Song et al ‘03).

Increasing alpha levels has a variety of desirable results. It reduces stress and anxiety, promotes relaxation and improves learning and concentration (Juneja et al ’99, Kim et al ‘01).

L-theanine is a tranquilliser, but quite unique in that it does not induce drowsiness or sedation at therapeutic doses. Rather, it promotes a state of calm alertness – a characteristic of traditional Japanese Zen masters which may have owed something to their regular consumption of green tea!

As this state of calm alertness is highly conducive for learning and performing complex tasks, l-theanine is increasingly used as a performance-enhancing supplement in exam and interview situations. Consumers have found that de-stressing and alertness is a winning combination in schools, colleges and business.

Psychologists and educationalists have discovered that l-theanine improves performance in children with ADD and ADHD, making this a genuinely therapeutic agent as well as a performance enhancer. Sports physiologists have shown that theanine improves recovery after physical stress (Weiss et al ‘01). And finally, Japanese psychologists have demonstrated that the feelings of calm induced by theanine are very helpful in combating the symptoms of PMS (Ueda et al ‘01).

If you want to experience this feeling of calm alertness for yourself, try a cup or two of Japanese green tea – but be aware that not all teas have the same theanine content. Bancha tea, for example, contains a mere 3mg per 80 ml cup; Sencha scores 10mg, but Matcha contains 36 mg.

Based on the results of clinical studies, L-theanine appears most effective in the range of 50-200 mg, with the effect being felt within 30 minutes and lasting for 8-10 hours. I would opt for a dose of 100 mg – which is 3 cups of Matcha tea.

The effects of theanine on the brain have been intensively studied for over 30 years (Kimura et al ‘71a, Kimura et al ‘71b, Kimura et al ’75, Shinozaki et al ’78, Kimura et al ’80, Kimura et al ’86, Nozawa et al ’95, Yokogoshi et al ‘98a, Yokogoshi et al ‘98b, Kakuda et al 2000, Yokogoshi et al 2000). These reports show that the up-regulation of alpha waves and the associated feeling of calm induced by theanine are due to its effects on neurotransmitters and neurotransmitter receptor sites in the central nervous system, which are very much in line with the observed effects.

In addition, it is known that L-theanine is involved in the formation of the stress inhibitory neurotransmitter (GABA). GABA influences the levels of two other neurotransmitters, dopamine and serotonin, and this produces the key relaxation effect (Mason R. 200 mg of Zen; L-theanine boosts alpha waves, promotes alert relaxation. Alternative & Complementary Therapies 2001,April; 7:91-95). It has also been found to exhibit an anti-hypertensive effect.

But there is even more. L-theanine may well find a useful role as a non-toxic anti-cancer agent. It inhibits the uptake of two other amino acids called l-cysteine and glutamate into cancer cells and thereby reduces their ability to make glutathione.

Glutathione is an important intra-cellular antioxidant, and when the cancer cell is deprived of glutathione it becomes much more vulnerable to free radical attack. As cancer cells are particularly vulnerable to free radicals this effect may be significantly therapeutic in itself.

But l-theanine has another anti-cancer property which complements the first.

It prevents cancer cells from excreting certain natural anti-cancer compounds, which can therefore accumulate inside the cancer cells more readily and kill them more easily (Sadzuka et al ’96, Sadzuka et al ’97, Sugiyama ’98, Sugiyama & Sadzuka ’99, Sadzuka et al 2000, Sadzuka et al ‘01). This is a significant benefit in itself, but there is even more: l-theanine also has the ability to reduce the toxic effects of chemotherapy (Sadzuka 2000, Sugiyama ’04).

There is nothing to prevent theanine from being widely incorporated into cancer therapy other than the resistance of drug companies and the blinkered perspective of cancer specialists.

Side-effects?
Tolerance, addiction or withdrawal problems have not been reported to occur with l-theanine. It is clearly superior in these respects to the benzodiazepines. For some unfathomable reason, however, our Eurocrat masters do not want us to be able to buy this compound in the EU just yet.

Fortunately, the obvious alternative to l-theanine in supplement form is Matcha Green Tea, which has been processed to retain the high l-theanine content, but to be palatable to the English taste. Various companies on the web sell Matcha Green Tea.

Green and black teas contain, in addition to theanine, a range of flavonoids which have well-defined cardio- and chemo-protective effects. These are described in the chapters on heart disease and cancer.

Natural Alternatives: The Adaptogens eg. Ginseng

Best known among the natural anti-stress remedies is Ginseng, or rather the ginsengs – for there are many of them. This is a class of herb known, collectively, as adaptogens; that is, they help you cope with stress.

A wide range of adaptogens are known in the folk literature from Panax ginseng (Chinese ginseng) to Eleutherococcus senticosus (Siberian ginseng) to Withania somnifera (Indian ginseng).

South America has Maca (Lepidium meyenii) and Suma (Pfaffia paniculata), Eastern Europe traditionally used briony root, the Chinese had Schizandra (Scizandra chinensis) and Astragalus (Astragalus membranaceus), and in India there is a long-established use of Gotu Kola (Centella asiatica).

These plants are all completely different species. In some cases the root is used, in others the leaves, or the bark. They may appear to have nothing in common – and yet they all share one key characteristic. They contain saponins, complex molecules that break down when eaten to produce sapogenins.

Sapogenins are rather like the steroid hormones we make in our own bodies. In fact, they are so similar that they are capable of binding to many of the steroid receptors on our cells. In the over-stressed individual, whose steroid receptors are being over-stimulated by high levels of cortisol, and who is suffering as a result, a course of Ginseng (or Maca, or Astragalus) can be helpful.

Side-effects?
However, there are potential pitfalls. We make and use a variety of different steroids in our bodies including the sex hormones, and the hormones which are involved in the control of water and salts, and hence blood pressure.

Although the receptors for these hormones are subtly different from the cortisol receptors, the sapogenins can activate these receptors to some extent. Long-term use of high dose adaptogens can, therefore occasionally cause adverse effects such as enlargement of the breasts – a particular problem in men (Palop et al ‘99) – and increased blood pressure (Martinez-Mir et al ’04).

Tolerance, addiction and withdrawal, however, do not occur. But if you use adaptogens, use them for limited periods.

Natural Alternatives: Herbal tranquillisers

Hops, Lime, Passionflower
These are rather more like the pharmaceutical tranquillisers in terms of their effects, in that they are used to calm, sedate and to induce sleep. Hops, lime and passionflower are all traditionally used, either as tinctures or tisanes, and all contain a group of compounds known as flavonoids.

Work at Imperial College in London has shown that these compounds enter the brain and exert their effect on a number of neurotransmitter systems (Dexter ’02). They are not quite as effective as the benzodiazepines, but as with the adaptogens, tolerance and addiction do not occur.

Valerian
Valerian (Valeriana officinalis) is a somewhat more potent but traditional tranquilliser and soporific that has been used for centuries in Britain and Western Europe (Blumenthal ’98, Schultz et al ’98, Fugh-Berman & Cott ‘99). The active compounds in valerian (Hendricks et al ’81, Houghton ‘99) act both on GABA (Santos et al ’94, Ortiz et al ‘99) and melatonin receptors.

Valerian extracts have been shown to be approximately as effective as the benzodiazepines in alleviating anxiety (Kamm-Kohl et al ’84, Kohnen & Oswald ’88, Andreatini et al ’02, Cropley et al ‘02), and insomnia caused by stress (Wheatley ‘01).

There is also a large and growing literature showing that Valerian can be used to improve sleep patterns in general (Leathwood et al ’82, Balderer & Borbely ’85, Leathwood & Chauffard ’85, Schultz et al ’94,Vorbach et al ’96, Schmitz & Jackel ’98, Donath et al 2000, Fussell et al 2000, Vonderheid-Guth et al 2000, Ziegler et al ’02).

A relatively recent review of these and other studies concluded that Valerian was indeed an effective remedy for anxiety and insomnia (Stevinson & Ernst 2000). Other clinicians concluded that Valerian was safe enough to be used to treat insomnia in children (Frances & Dempster ‘02).

Side-effects?
Although they exert similar effects, Valerian and the benzodiazepines clearly act in slightly different ways because, although a degree of tolerance to Valerian can occur, addiction has not been reported. In the interests of balance, it is only fair to point out that there is one report of delirium linked to Valerian withdrawal (Garges et al ‘98), but this finding has not been duplicated.

In fact, and despite its occasional use as a poison in lurid TV dramas, Valerian is very safe indeed; and may have a role in helping benzodiazepine addicts through their withdrawal symptoms (Andreatini & Leite ’94, Poyares et al ‘02).

Nonetheless, because human safety data is limited, I would not recommend Valerian use during pregnancy and breastfeeding. The folk literature does not consider these to be contra-indications, but it is best to adopt the precautionary principle here.

Kava Kava
Kava Kava (Piper methisticum) is the most potent known herbal tranquilliser. Double-blind studies show it to be as clinically effective as Valium (Lindenberg & Pitule-Schodel ’90,Warnecke et al ’90, Kinzler et al ’91, Woelk et al ’93, Volz & Kieser ’97, Malsch & Klement 2000, Connor & Davidson ‘02), as confirmed by a recent meta-analysis (Pittler & Ernst 2000).

Long-established in Polynesia where it has a history of ceremonial use, it was introduced into the USA and Europe in the ’90s and rapidly became the most popular of the herbal anxiolytics. It was so effective that it began to hurt drug sales, and it was not long before the anti-Kava propaganda campaigns started.

A rather dubious list of 84 cases was drawn up which showed that kava kava might cause problems including liver damage (Bilia et al ’02, Mesegeur et al ’02, Morbidity & Mortality ’03); and despite serious doubts about the integrity of this list, the regulatory authorities banned kava kava in the EU towards the end of 2002.

The supplement companies, however, backed up by a growing number of toxicologists and herbalists who simply did not believe that kava kava was dangerous, subsequently launched an appeal.

Crucially, the campaigners looked at the 84 cases on which the ban rested. In some of the 84 cases many other drugs were being taken including alcohol. And in others, it appeared that the herbal extracts themselves had been adulterated. Traditionally the root of the kava plant is used, but due to the fast-growing demand for kava extract some manufacturers had started using the bark also. This was found to contain the alkaloid pipermethystine which could, if taken in large doses, cause liver damage.

The remedy was straightforward – although it clearly should have been instigated from the start. The companies marketing kava kava self-regulated; plant growth was stepped up; and a more highly standardised approach to extraction emerged.

In 2003, as part of the fight against the ban, campaigners produced a report on the safety of the herb. The report by Berlin-based Phytopharm Consulting concluded that kava is a safe and effective herbal medicinal product. It also found the measures taken by European health authorities to be inappropriate and unjustified.

For example, kava kava does not cause liver damage in animal models, even at enormous doses (Singh & Devkota ’03); and in Polynesia, where it has been used for centuries, there is no history or evidence of liver damage either (Moulds & Malani ’03).

SUMMARY

As there are now so many natural and non-addictive alternatives to benzodiazepines, there is little reason or excuse for doctors to continue to make addicts. In addition, if surgeries and pharmacies stopped stocking these addictive drugs, the black market for benzos would start to disappear. There is little to prevent this, other than the drug industry’s continuing prioritisation of the interests of its stock-holders over those of patients.

Of the natural remedies for stress the case for l-theanine via Matcha Green Tea is strong, because of the other potential benefits and because it is classed as a food rather than a herb – and therefore subject to rather more stringent regulations. An alternative – perhaps even an addition – might be the milk peptide, Lactium.

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