Lesdoup

Wound Healing

2015-06-09T17:16:00.003-07:00

Inflammatory Phase (Day 0-5)
The healing response is initiated at the moment of injury. Surgical or traumatic wounds disrupt the tissue architecture and cause haemorrhage. Initially, blood fills the wound defect and exposure of this blood to collagen in the wound leads to platelet degranulation and activation of Hageman factor [1]. This in turn sets into motion a number of biological amplification systems including the complement kinin and clotting cascades and plasmin generation. These serve to amplify the original injury signal and lead not only to clot formation, which unites the wound edges, but also to the accumulation of a number of mitogens and chemoattractants at the site of wounding [2].

Production of both kinins and prostaglandins leads to vasodilatation and increased small vessel permeability in the region of the wound [3]. This results in oedema in the area of the injury and is responsible for the pain and swelling which occurs early after injury. Within 6 h, circulating immune cells start to appear in the wound. Polymorphonuclear leucocytes (PMN) are the first blood leucocytes to enter the wound site. They initially appear in the wound shortly after injury and subsequently their numbers increase steadily, peaking at 24-48 h [4]. Their main function appears to be phagocytosis of the bacteria which have been introduced into the wound during injury. The presence of PMN in the wound following injury does not appear to be essential in order for normal
wound healing to take place [5, 6], with healing proceeding normally in their absence provided that bacterial contamination has notoccurred. In the absence of infection, PMN have a relatively short life span in the wound and their numbers decrease rapidly after the third day [7].

The next cellular, immune element to enter the wound are macrophages. These cells are derived from circulating monocytes by a combination of migration and chemotaxis. They first appear within 48-96 h post-injury and reach a peak around the third day postinjury [4]. These macrophages have a much longer life span than the PMN and persist in the wound until healing is complete. Their appearance is followed somewhat later by T lymphocytes, which appear in significant numbers around the fifth day postinjury, with peak numbers occurring about the seventh day after injury. In contrast to PMN, the presence and activation of both macrophages and lymphocytes in the wound is critical to the progress of the normal healing process [8, 9]. Macrophages just like neutrophils phagocytose and digest pathological organisms and tissue debris. In addition, macrophagesrelease a plethora of biologically active substances. Many of these substances facilitate the recruitment of additional inflammatory
cells and aid the macrophage in tissue decontamination and debridement; in addition growth factors and other substances are also released which are necessary for the initiation and propagation of granulation tissue formation. These intercellular transmitters are known collectively as cytokines.

Proliferative Phase (Day 3-14)

In the absence of significant infection or contamination the inflammatory phase is short, and after the wound has been successfully cleared of devitalized and unwanted material it gives way to the proliferative phase of healing. The proliferative phase is characterized by the formation of granulation tissue in the wound. Granulation tissue consists of a combination of cellular elements,
including fibroblasts and inflammatory cells, along with new capillaries embedded in a loose extra cellular matrix of collagen, fibronectin and hyaluronic acid. Fibroblasts first appear in significant numbers in the wound on the third day post-injury and achieve peak numbers around the seventh day [4]. This rapid expansion in the fibroblast population at the wound site occurs via a combination of proliferation and migration [10]. Fibroblasts are derived from local mesenchymal cells, particularly those associated with blood vessel adventitia [11], which are induced to proliferate and attracted into the wound by a combination of cytokines produced initially by platelets and subsequently by macrophages and lymphocytes (Table 1). Fibroblasts are the primary synthetic element in the repair process and are responsible for production of the majority of structural proteins used during tissue
reconstruction. In particular, fibroblasts produce large quantities of collagen, a family of triple-chain glycoproteins, which form the main constituent of the extracellular wound matrix and which are ultimately responsible for imparting tensile strength to the scar. Collagen is first detected in the wound around the third day post-injury [12, 13], and thereafter the levels increase rapidly for approximately 3 weeks. It then continues to accumulate at a more gradual pace for up to 3 months post wounding [10]. The collagen is initially deposited in a seemingly haphazard fashion and these individual collagen fibrils are subsequently reorganized, by cross -linking, into regularly aligned bundles oriented along the lines of stress in the healing wound. Fibroblasts are also responsible for the production of other matrix constituents including fibronectin, hyaluronic acid and the glycosaminoglycans [14]. The process of fibroblast proliferation and synthetic activity is known as fibroplasia.

Revascularization of the wound proceeds in parallel with fibroplasia. Capillary buds sprout from blood vessels adjacent to the wound and extend into the wound space. On the second day post-injury, endothelial cells from the side of the venule closest to the wound begin to migrate in response to angiogenic stimuli. These capillary sprouts eventually branch at their tips and join to form
capillary loops, through which blood begins to flow. New sprouts then extend from these loops to form a capillary plexus [15, 16]. The soluble factors responsible for angiogenesis remain incompletely defined. It appears that angiogenesis occurs by a combination of proliferation and migration. Putative mediators for endothelial cell growth and chemotaxis include cytokines
produced by platelets, macrophages and lymphocytes in the wound [17, 18], low oxygen tension [19], lactic acid [20] and biogenic amines [21]. Of the potential cytokine mediators of neovascularization basic fibroblast growth factor (bFGF), acidic FGF (aFGF), transforming growth factors -aand b(TGF-aand -b) and epidermal growth factor (EGF) have all been shown to be potent stimuli for new vessel formation [22-24]. FGF, in particular, has been shown to be a potent inducer of in vivo neovascularization [25, 26]

While these events are proceeding deep in the wound, restoration of epithelial integrity is taking place at the wound surface. Reepithelialization of the wound begins within a couple of hours of the injury. Epithelial cells, arising from either the wound margins or residual dermal epithelial appendages within the wound bed, begin to migrate under the scab and over the underlying viable
connective tissue. The epidermis immediately adjacent to the wound edge begins thickening within 24 h after injury. Marginal basal cells at the edge of the wound loose their firm attachment to the underlying dermis, enlarge and begin to migrate across the surface of the provisional matrix filling the wound. Fixed basal cells in a zone near the cut edge undergo a series of rapid mitotic divisions, and these cells appear to migrate by moving over one another in a leapfrog fashion until the defect is covered [27, 28]. Once the defect is bridged, the migrating epithelial cells loose their flattened appearance, become more columnar in shape and increase in mitotic activity. Layering of the epithelium is re-established and the surface layer eventually keratinized [29]. Reepithelialization is complete in less than 48 h in the case of approximated incised wounds, but may take substantially longer in the case of larger wounds where there is a significant tissue defect. If only the epithelium is damaged, such as occurs in split thickness skin graft donor sites, then repair consists primarily of re-epithelization with minimal or absent fibroplasia and granulation tissue formation. The stimuli for re-epithelization remain incompletely determined, but it appears that the process is mediated by a
combination of loss of contact inhibition, exposure of constituents of the extracellular matrix, particularly fibronectin [30], and by cytokines produced by immune mononuclear cells [31]. EGF, TGF-b, bFGF, platelet-derived growth factor (PDGF) and insulinlike growth factor-l(IGF-l) in particular, have been shown to promote epithelialization [32].

Maturation Phase (Day 7 to I Year)

Almost as soon as the extracellular matrix is laid down, its reorganization begins. Initially, the extracellular matrix is rich in fibronectin, which forms a provisional fibre network. This serves not only as a substratum for migration and ingrowth of cells, but also as a template for collagen deposition by fibroblasts [33]. There are also significant quantities of hyaluronic acid and large
molecular weight proteoglycans present, which contribute to the gel-like consistency of the extracellular matrix and aid cellular infiltration. Collagen rapidly becomes the predominant constituent of the matrix. The initially randomly distributed collagen fibres become cross -linked and aggregated into fibrillar bundles, which gradually provide the healing tissue with increasing stiffness and tensile strength [34]. After a 5-day lag period, which corresponds to early granulation tissue formation and a matrix largely composed of fibronectin and hyaluronic acid, there is a rapid increase in wound breaking strength due to collagen fibrogenesis. The subsequent rate of gain in wound tensile strength is slow, with the wound having gained only 20% of its final strength after 3
weeks. The final strength of the wound remains less than that of uninjured skin, with the maximum breaking strength of the scar reaching only 70% of that of the intact skin [34].
This gradual gain in tensile strength is due not only to continuing collagen deposition, but also to collagen remodelling, with formation of larger collagen bundles [35] and alteration of intermolecular crosslinking [36]. Collagen remodelling during scar formation is dependent on both continued collagen synthesis and collagen catabolism. The degradation of wound collagen is controlled by a variety of collagenase enzymes, and the net increase in wound collagen is determined by the balance of these opposing mechanisms. The high rate of collagen synthesis within the wound returns to normal tissue levels by 6-12 months [37], while active remodelling of the scar continues for up to 1 year after injury and indeed appears to continue at a very slow rate for life.
As remodelling progresses, there is a gradual reduction in the cellularity and vascularity of the reparative tissue which results in the formation of a relatively avascular and acellular collagen scar. Grossly this can be observed as a reduction in erythema associated with the earlier scar and some reduction in the scar volume, resulting in a pale thin scar. This is normally a desirable feature of
healing; however, in some cases shrinkage of the scar may give rise to an undesirable reduction in skin mobility resulting in contracture.
Wound contraction, i. e. inward movement of the wound edge, is a further important element in the healing process and should be distinguished from contracture. Sharply incised wounds without significant tissue loss, approximated early after injury, heal rapidly without the need for significant reduction in the wound volume. Such wounds are described as having healed by primary intention.
Large wounds, however, particularly those associated with significant tissue loss, heal by secondary intention, with granulation tissue gradually filling the defect and epithelization proceeding slowly from the wound edges. Contraction of the wound edges can lead to a significant reduction in the quantity of granulation tissue required to fill the wound defect and a reduction in the area
requiring reepithelization, with a consequent reduction in scar volume. Contraction is only undesirable where it leads to unacceptable tissue distortion and an unsatisfactory cosmetic result. Although contraction normally accounts for a larger part of overall wound closure in looseskinned animals, it still accounts for a significant proportion of the healing process in man, particularly
in areas where the skin is not tightly bound down to underlying structures, such as on the back, neck and forearms. Initially following injury, where the wound edges are not approximated, there is a slight retraction of the wound edges due to the release of normal elastic tension in the skin, with a resultant increase in wound volume. The wound area starts to decrease rapidly from the
third day onwards. While this is due in part to reepithelization, the main reason is an inward movement of the uninjured skin edges. Wound contraction usually begins around the fifth day postwounding and is complete by 12-15 days after wounding [38-40]. Fibroblasts within the wound appear to be responsible for providing the force for this contractile activity [41]. It was initially felt that specialized fibroblasts called myofibroblasts provided the motive force for wound contraction via a musclelike cell contraction [42-

More recent studies reveal that wound contraction occurs as a result of an interaction between fibroblast locomotion and collagen reorganization [41, 45]. The contraction is thought to be mediated via the attachment of collagen fibrils to cell surface receptors [46], with the resulting tractional forces generated by cell motility bringing the attached collagen fibrils closer together and
eventually compacting them [47].
The regulation of wound contraction remains poorly defined. Information regarding the effects of specific cytokines on contraction is limited and often conflicting. TGF-bhas been found to promote contraction even in the absence of serum [48, 49]; PDGF has also been found to either increase contraction [50] or have no effect [49], while both FGF and EGF have been found by different authors to either have no effect or cause a moderate enhancement of contraction [48-50].

Scar Formation
As mentioned previously, the process of wound healing is essentially similar in all tissues and is relatively independent of the mode of injury; however, slight variation in the relative contribution of the different elements to the overall result may occur. The final product of the healing process is a scar. This relatively avascular and acellular mass of collagen serves to restore tissue continuity,
strength and function. Delays in the healing process cause the prolonged presence of wounds, while abnormalities of the healingprocess may lead to abnormal scar formation. Successful completion of wound healing may not always yield the desired clinical result, particularly where the final cosmetic appearance of the scar is of primary importance.

12 keys unaddicting your brain

2014-06-12T16:12:00.000-07:00

In this part we explain the 12 Keys that have proven most helpful to people kicking their addiction. Think of it as a boot camp for your brain. The 12 Keys are simple steps you can take to give your brain, and your psyche, the equivalent of a trip to the health farm. And it works. By eating healthy foods and taking the absolute optimum amount of key nutrients you reprogramme your brain and body chemistry so that you quickly start to experience a state of natural energy, clarity and steady mood – in effect an enjoyable natural high. Because of this, you’ll find the desire to use an addictive substance far less strong.
Don’t underestimate the power of your brain

It is important to remember that there is no ‘1 Key’ solution to addiction. If you’ve been using addictive substances for many years, possibly in large quantities, your brain will not simply be ‘reset’ by eating a so-called well-balanced diet. Similarly, if you’ve experienced major stresses and traumas in life you don’t just recover by leading a balanced life. There is damage that needs to be undone. You have to reprogramme your mind and rebuild your brain. If you’ve seriously scrambled your brain, just sitting in a room and talking about your past isn’t going to unscramble it.
The bottom line is that if your brain is programmed for addiction, with all the will in the world, and the best counselling, and even some of the new addiction drugs that make you feel sick if you use the drug of your choice, nothing is stronger than the impulse of your brain telling you that your survival depends on having tis substance. Biological urges are immensely strong. You try not breathing, or not peeing, for example. We take our hats off to those who have quit when all the cells in their body are screaming for a cigarette, a drink or a drug. That’s definitely the hard track.
The easier track is to work with your brain’s natural design, not against it, by restoring the imbalance, not with drugs, but with the very nutrients that your brain has evolved to use over millions of years. This approach not only reprogrammes your brain and your body’s chemistry to make you feel good naturally, but it also reprogrammes how you react to the triggers that lead you to take an addictive substance. As your brain, mood, concentration and energy start to come back to life so does your capacity for learning and resolving psychological or life conflicts that may be part of you getting stuck in some level of addiction. Hence counselling is much more effective in optimally nourished people. Although psychological issues, such as feeling completely stressed or depressed, can lead you into addiction, once you are in it, the brain’s chemistry becomes reprogrammed, and simply solving the reason for your stress or depression, and avoiding the substance, doesn’t reset your brain’s chemical balance. The best way to achieve this is through the programme presented in this book.
Success is proven

This isn’t just talk. Our approach works in the real world. For example, in one treatment centre, Bridging The Gaps in Winchester, Virginia, which has incorporated these 12 Keys into their treatment agenda, along with intravenous nutrient therapy, the success rate has gone through the roof. We followed up 23 clients one year after they had started the equivalent of this How to Quit approach to quit their serious drug and alcohol addictions, and found that of the 23, 21 were clean and sober. That’s an incredible 91 per cent success rate! The usual one year success rate (meaning still clean and sober) for other methods of quitting is around 20 per cent. Of the 23 participants, 16 (70 per cent) had not even had a brief relapse – not a single drink or use of any drug.
Using the 12 Keys

The 12 Keys to Unaddicting Your Brain are designed to help you understand the solutions that are right for you. The first six define what ‘optimum nutrition’ really means in terms of unaddicting your brain: how to find out which amino acids will most rapidly reduce your abstinence symptoms; the kind of foods and supplements to take to get the best intake of essential fats, vitamins and minerals; and how to improve your ability to digest and absorb these nutrients. The next three chapters on getting a good night’s sleep, solving hidden food allergies and rejuvenating your liver, will be more applicable to some readers than others, but please read them all to see if they address issues that relate to you. The last three chapters explain what you can do to raise your feelgood endorphins naturally, generating vital energy and emotional healing – all have the effect of increasing your energy.
Get support

Although everything in this programme can be done at home, if you have a serious addiction we encourage you to work with a team of health professionals, including a nutritional therapist and psychotherapist, or a treatment centre that uses most of these 12 Keys to Unaddicting Your Brain. If your treatment centre choice does not incorporate our How to Quit nutrition approach you can always also attend, as an outpatient, the Brain Bio Centre in Richmond, Surrey (see Resources) to find your ideal nutrition prescription.
Add value to your programme

Whereas the optimum nutrition approach to reversing addiction is a vital missing piece we do not believe that it is the only piece of the jigsaw and recommend you do anything and everything that works for you. There is no contradiction to adding our How to Quit programme to any other method or technique for reversing your addiction. (If you are on prescribed medication please make sure you read Chapter 7 as there are some amino acids that should not be taken alongside certain drugs.)
Moving on

In Part 3 you’ll find out which of the keys we outline here will make the biggest difference to you, depending on which substances you want to quit

The effect of cigarette

2014-05-30T00:13:00.000-07:00

‘Man is a knackered ape’, said one child in an exam howler (it should have been ‘naked ape’), but it can so easily be true. When we are under touch stress and we find it hard to unwind and switch off, relaxants such as alcohol, cannabis, or even sleeping pills, sound attractive. It’s so easy to get caught in that trap.
For many people the first taste of addiction comes from seeking something that will increase their energy or decrease their stress, depression and anxiety, which is often caused by sub-optimum nutrition, a lack of sleep and working or playing too hard. At some point you’ll taste the sweetness of sugar and feel its energy-giving effects; or have a strong tea or coffee and feel the lift; or have a cigarette and feel the elevating and relaxing buzz; or the unwinding effect of a glass of wine. Stress itself is a stimulant, promoting the release of adrenalin and cortisol, and many of us become addicted to stress, panic and living on the edge. At least you feel alive – kind of.
When occasional use becomes a need

To begin with this is no big deal – just the occasional use of a substance to change how you feel. But, as we learned in the last chapter, your brain’s chemistry is already changing. You become less sensitive to the substance and therefore need more of it to feel good. Some stop at that one or two coffees a day, or that occasional cigarette, but others don’t. Many people end up hooked and ‘needing’ 20 cigarettes or a dozen cups of tea or coffee to feel kind of normal. For some, even this isn’t enough and the combination of down-regulation (becoming increasingly insensitive to the substance and needing more) and consequent reward deficiency (craving a dopamine high) leads to the desire to try something stronger – maybe cocaine for that extra kick or a more potent relaxant such as more alcohol, or even Valium or heroin if that isn’t enough.
Then there’s the other side of the fence, when you’ve quit something you had become extremely addicted to, such as alcohol, but have substituted it with loads of sugar, stimulant drinks and cigarettes. Although this appears to be a step in the right direction this means your brain chemistry is still out of balance.
The more you have, the more you want

For many people the slippery road to dependency starts with stress, sugar, cigarettes or stimulants such as caffeinated drinks. These all have similar biochemical effects by stimulating the brain’s trio of inbuilt stimulants: dopamine, noradrenalin and adrenalin. These stimulants give you get-up-and-go – at least temporarily – but in the long run they make you more stressed and exhausted.
They are actually ‘worker drugs’, and only really became popular and excessively consumed in the Industrial Revolution, as people started to work harder and harder, driven by the culture of capitalism and competition.
The trouble is, as we have already explained, the more you have the more you want. That one cup of coffee turns into two, then three, then there is the ‘speciality’ coffee that you make yourself in an elaborate ritual that, behind the scenes, means you knock back a triple espresso. That occasional cigarette turns into ten, then 15, then 20 or more. Sweet foods become a constant craving. You become more tired, more stressed and more in need of a fix. Then you need alcohol to relax.

The vicious cycle of stress, stimulants and fatigue

The exhaustion epidemic

Never mind the Industrial Revolution, the technological revolution we live in today has spawned a world that never sleeps. Television, the Internet and even the stock market call to us 24 hours a day, seven days a week. When we shave an hour off our sleep, we feel we’ve gained some small advantage.
Many of us are also trying to keep impossible schedules of work and family responsibilities. And it has a cumulative effect. You struggle to find time with your children, friends and colleagues, not to mention your partner. You’re less alert than you’d like, feeling drowsy as the day wears on, dozing off if you sit down to read or watch TV in the evening. When you finally do get together with your partner at bedtime, neither of you has the energy for anything more than falling asleep.
We turn to chemicals to help us through the day

Too often today we become reliant on chemical ‘helpers’ to keep us going: the frequent coffee breaks, the chocolate bar to satisfy our hunger when we have no time to eat, the cigarette to calm our nerves.
Heavy use of substances like coffee, chocolate and cigarettes can lead to reward deficiency.

Although we might recognise the problems that are created when we use illegal drugs such as heroin, or if we drink to excess, smoke or become hooked on strong prescription drugs, we usually don’t recognise that we can become addicted to caffeine or sugar and that these too can have serious repercussions for our health – dominating our lives and making us feel under par. We believe that we just need a little boost sometimes to get us through the day – despite the fact that if we’re low on energy it might be because we are dependent on stimulants.

How dependent are you on stimulants?

To get an idea of how depleted your natural energy might be and how dependent you are on stimulants, check yourself out in the following questionnaire:
QUESTIONNAIRE: check your energy

Yes No
1. Do you have trouble getting up in the morning?

2. Do you rely on a cup of coffee to get you going in the morning?

3. Do you feel tired all the time?

4. Do you often feel foggy, fuzzy or dull?

5. Do you have trouble concentrating?

6. Do you use sugar, caffeine (tea, coffee, caffeinated cola drinks) or a cigarette as a pick-me-up throughout the day?

7. Are you often irritable or angry, for no apparent reason?

8. Do your moods seem to go up and down for no apparent reason?

9. Are your mood swings often relieved by food, especially sweets?

10. Do you have trouble falling asleep at night?

11. Do you have headaches or shaky feelings that are relieved by sugar, caffeine or cigarettes?

12. Do you suspect you’re addicted to coffee, caffeinated cola, or cigarettes?

13. Do you find yourself operating from crisis to crisis?

14. Are you drawn to thrills, danger and drama in your life?

Score 1 for each ‘yes’ answer.
Total score:

Score

Below 5

You’re doing fine. We all have our moments – bad moods, feeling tired or foggy – when we are in need of a pick-me-up.
Between 5 and 10

You are showing signs of an overdependence on stimulants to keep you going. This next section will explain what is happening in your body, and how to make healthier choices.
More than 10

You are seriously hooked on stimulants, and it is affecting your mental and physical health. It’s important for you to take yourself off them. We will show you how in Part 2.
The see-saw of stimulants and relaxants

If you give in to your cravings for stimulants, it does not necessarily mean you are weak or ‘bad’, but simply that your chemistry is controlling you. You need the right fuel – foods, vitamins and other micronutrients – to run your body’s engine (see Part 2). You also need sufficient sleep to restore body and mind and maintain your energy level. When you turn to stimulants to give you energy, however, they further deplete your already bankrupt system.
The reason they work in the short term but not in the long term is because of what they do to your blood sugar balance, as well as the balance of your neurotransmitters and hormones.
Stress, sugar and stimulants all raise your blood sugar, which can give you a short-term boost in energy. But, in time, your blood sugar level becomes more and more unstable.

One of the reasons for this is that the body becomes less and less sensitive to the hormone insulin, which controls your blood sugar level. So now you need more stimulants to keep you going. Eventually you become dependent on stimulants. It’s a vicious cycle of stress, overuse of stimulants and fatigue. The end result is daily craving – and exhaustion.
Some people start using more potent stimulants such as amphetamines and cocaine to get an extra lift. The more stimulants you use, the harder it is to relax and sleep soundly. Then you need relaxants such as alcohol, sleeping pills, tranquillisers and marijuana to bring you down. This see-saw lifestyle affects performance, promotes stress and depletes your energy.
Handle with care: popular stimulants

As you can see from the diagram on page 90, all stimulants work by mimicking or triggering the release of the three neurotransmitters: dopamine, adrenalin and noradrenalin. That’s what makes you feel motivated and upbeat. We learned in Chapter 3 how down-regulation in the brain eventually puts a stop to the fun of getting high. That’s exactly what happens with stimulants. This overstimulation leads to down-regulation, as receptor sites for dopamine, adrenalin and noradrenalin start to shut down. You keep needing more of the product to l the same effect. But how much is too much, and are there some stimulants we can take safely in moderation?

How stimulants work

Although a substance can be good in one context, it can be harmful in another. In one short-term experiment, coffee was shown to heighten alertness, but you already knew that, didn’t you? And now you know that something can have benefits in the short term but be harmful in the long term.
We’ll deal with these issues as we discuss each substance in detail. But for now let us say that some stimulants are never recommended, whereas others can be acceptable in moderation, depending on the situation.
Sugar: toxic treat

Sugar is a fairly recent entry into the stimulant game. Of course it’s always been available in natural sources such as fruit, with its slow-releasing fructose and fibre. Refined sugar, however, only came in with the Industrial Revolution. Yet today, we can hardly picture a celebration without sweet treats – birthday and wedding cakes, Christmas puddings, Easter chocolates.
How can such a delicious, seemingly harmless children’s treat be so damaging? Rapidly absorbed and broken down into molecules of glucose, it quickly reaches the brain, producing feelings of ‘comfort’ or ‘energy’. Sugar bingeing looks a lot like any other addiction: tolerance develops, and you need more to get the same effect. How serious is that? Furthermore, there’s a strong link between sugar addiction and alcoholism. An illustration of this is a study by addiction researchers from University of North Carolina at Chapel Hill.31 In one study they asked 20 abstinent alcoholic men and 37 non-alcoholic men to taste five sugar solutions. The solutions ranged from not sweet at all to very sweet. Sixty-five per cent of alcoholics preferred the sweetest solution compared to only 16 per cent of non-alcoholics. In another study they found that 19 pairs of twin brothers shared a similar liking for sweets and alcohol despite having quite different life experiences.
The downside of sugar

Sugar is bad for you. Although a valuable fuel for our cells, it can be toxic when consumed in excess, often causing damage to the arteries, kidneys, eyes and nerves.
The body tries to get it out of the blood as quickly as possible, but this can then cause a ‘rebound’ low blood sugar with its own set of problems. Some people feel stimulated immediately after eating it, then become cranky and finally go into a low blood sugar slump.

Individuals who reported drinking more alcohol on occasion and having more alcohol-related problems of No had problems controlling how many sweets they ate.

They were more likely to report urges to eat sweets and craving for them. They also were more likely to report this craving when they felt nervous or depressed, and they believed eating sweets made them feel better. This suggests that the craving for sweets and the urge to drink may stem from the same genes, possibly reward deficiency genes.
Caffeine: brewing up trouble

Found in over a hundred plants, caffeine is consumed primarily in drinks. A half-dozen caffeine-containing plants are more widely used than all other herbal materials combined!
Over a thousand years ago, Muslims used coffee for religious rituals. When the stuff finally reached Europe in the seventeenth century it was seen by the authorities as a dangerous drug. Nonetheless, coffee houses spread, as did dependence on this new drug. The rest is history. Together with tea, it comprises 97 per cent of worldwide caffeine consumption. Some parts of the world use other forms of caffeine – mate, guarana and kola nut – which are now becoming more popular in the West.
Caffeine was first isolated from coffee in 1821. The effects of coffee are more potent than those of caffeine alone since it contains two other stimulants: theophylline and theobromine.
How does it work?

Caffeine boosts mood and energy by blocking the receptors for a brain chemical called adenosine, whose function is to stop dopamine release. With less adenosine activity, you increase dopamine and adrenalin. You then feel alert, motivated and stimulated, although some people will feel uncomfortable and jittery. In 30 to 60 minutes, caffeine reaches its peak concentration. It is then inactivated by the liver, with only half its peak level left after four to six hours. Of course, if your liver function is poor you don’t do this so well.
So where’s the danger? Caffeine is highly addictive. Research shows that consuming as little as 100mg a day can lead to withdrawal symptoms when you stop, including headache, fatigue, difficulty concentrating and drowsiness. It’s worth knowing that while a small cup of instant coffee may contain less than 100mg of caffeine, a large ‘designer’ coffee can contain as much as 500mg – five times the ‘addictive’ dose. Decaf has much less – less than 1mg in a cup.
The downside of caffeine

Overstimulation of the central nervous system, leading to increased risk of heart attacks, irritability, insomnia and rapid and irregular heartbeats.
Elevated blood sugar and cholesterol levels.
Heartburn and other gastrointestinal problems.
Increased risk of fibrocystic breast disease.
Diuresis (excessive urination), which can lead to dehydration.
Used during pregnancy, it increases the risk of birth defects.
Contains tars, phenols, and other carcinogens.
Pesticides are used during growing most coffee beans, and these contain cancer-causing compounds (so choose organic if you choose it at all).

At best, we can say that coffee has minor short-term mental and emotional benefits, but these are not sustained. A study published in the American Journal of Psychiatry observed 1,500 psychology students divided into four categories depending on their coffee intake: abstainers, low consumers (who drank one cup or equivalent a day), moderate (one to five cups a day) and high (five or more cups a day). On psychological testing, the moderate and high consumers had higher levels of anxiety and depression than the abstainers, and the high consumers had a higher incidence of stress-related medical problems coupled with lower academic performance.32
The bottom line? Use in moderation, but preferably not at all.
Tea: not always refreshing

In Britain three times more tea than coffee is drunk every day. In the US the figures are reversed. You can guess why by recalling the historic Boston Tea Party, which preceded the American Revolution. Rather than pay a tea tax to their oppressors across the sea, the colonists dumped boxes of imported tea from British ships into the harbour – and haven’t had much taste for it since.
Tea’s stimulating effects come from caffeine, theobromine and theophylline, the same compounds as in coffee. Because of different methods of preparation and the many varieties of the cultivated plant, the average caffeine content of tea ranges widely. Tea contains less caffeine than coffee. However, even when caffeine levels are matched, the effects of tea and coffee on mood are very different, suggesting that there is another component in tea that may be responsible.33 This may be because tea also contains the natural amino acid L-theanine, a relaxant. Early research suggests that 50mg L-theanine naturally stimulates activity in the brain, known as alpha waves, which are associated with a relaxed but alert mental state.34 A typical cup of tea contains 14–18mg of L-theanine.35 Green tea contains even more, and also has much higher levels of health-promoting antioxidant polyphenols. In addition, green tea may help prevent liver damage and lower the risk of death from a number of diseases, including heart disease and strokes.

Case study PAUL

Paul is a good example of what happens when you have too many stimulants. He was drinking 20 cups of tea a day, each with two sugars, and smoking over 20 cigarettes a day. He had no drive or motivation in life and lacked confidence in himself. After following a low-GL diet (as explained in Chapter 11), plus the right supplements, he has given up cigarettes and caffeine. ‘I feel 100 per cent better. My energy is great. I’m not tired. I feel motivated. My skin is transformed. It’s made a major difference.’

The downside of tea

A strong cup of tea contains as much caffeine as a weak cup of coffee – with all the attendant risks (see page 94).
The tannin content interferes with absorption of minerals.

We recommend tea in moderation, meaning two cups a day, or three cups of green tea.
Colas and caffeinated drinks: ‘cocaine in a can’

A cola drink contains about half the caffeine found in a cup of coffee. The original Coca Cola even contained small amounts of coca (cocaine) – hence the name. Today’s drinks usually contain sugar and colourings, which also act as stimulants. Maybe worse, diet drinks contain the artificial sweetener aspartame (Nutra Sweet), which can be toxically overstimulating to the brain. We have seen people who thought they were ‘going crazy’ with anxiety, insomnia and disordered thinking magically recover when they stopped their diet drinks. Ironically, although touted as a diet product, they can actually cause weight gain. (See www.dorway.com/blayenn.html for information on this chemical.)
However, caffeinated soft drinks that are even stronger, with names such as Jolt or Red Bull, can contain up to 80mg of caffeine per can (that’s more than a weak cup of coffee) and that increases their kick and addictiveness. Shades of the tobacco industry! Red Bull shot to fame in the UK after a newspaper article described it as ‘cocaine in a can’. Children and young people are drinking large amounts of these drinks, especially relative to their weight, thereby exposing their developing brains and bodies to a hazardous substance. Their use, together with alcohol, allows a person to drink more because they stay awake. Never mind illicit drugs, consuming too much junk food and high-sugar, high-caffeine drinks can lead to serious health problems and addictions in children. We often encounter diet cola addicts.

Case study DENISE
Denise became so addicted to Diet Coke she bought a small fridge to keep by her bed so that when she woke up at night she could reach out and grab a can! Coca Cola’s corporate agenda has been to have their products ‘within a hand’s reach osire’ and, in the case of Denise, they had certainly achieved their goal! At her worst she was knocking back 20 a day. She had irritable bowel syndrome (IBS), frequent colds, low energy, poor sleeping and a desire to lose some weight. Her periods were also irregular, often heavy, with cramping. She had headaches twice a week and took painkillers regularly. After three months of following our nutritional programme not only is she caffeine-free, but all her health problems have resolved – and she has lost weight.

The downside of colas

Colas contain caffeine – with all its attendant risks (see The Downside of Caffeine, page 94).
Sugar and colouring are added stimulants, whereas aspartame in diet versions can toxically overstimulate the brain.
New drinks aimed at young people have even higher levels of caffeine.

Other sources of caffeine

Another source of caffeine is guarana, which is sold as a herbal stimulant. The seeds and leaves of the climbing shrub native to Brazil and Uruguay are high in caffeine. A dried paste made chiefly from the crushed seed of guarana has a relatively high caffeine content, ranging from 2.5 to 5 per cent and averaging about 3.5 per cent. To determine how much caffeine there is in any product, you must do your maths. You multiply the total weight of the capsule or powder by the percentage of caffeine or guarana to get the number of milligrams of caffeine per dose. The conclusion regarding its use? Like coffee, it can be overstimulating, and have the same ill effects.
Some medications for the relief of headaches, such as Anadin, contain caffeine. Other caffeine tablets such as Pro Plus and the herb guarana are sold outright as stimulants. With the exception of a moderate intake of caffeine in tea we recommend you limit your intake of caffeine to no more than 100mg a day.
Here are the caffeine levels of some common products:
CAFFEINE BUZZOMETER

>PEP
Coca-Cola Classic 350ml (12fl oz) 35mg
Diet Coke 350ml (12fl oz) 47mg
Red Bull 250ml (8.3fl oz) 76mg
Hot cocoa 150ml (5fl oz) 10mg
Coffee, instant 150ml (5fl oz) 40–105mg
Coffee, espresso, cappuccino, latte 50–175mg
Coffee, filter 150ml (5fl oz) 102–200mg
Coffee, Starbucks (grande) 150mg
Decaffeinated coffee 150ml (5fl oz) 0.3mg
Tea 150ml (5fl oz) 20–100mg
Chocolate cake (1 slice) 20–30mg
Bittersweet chocolate 28g (1oz) 5–35mg
Pro Plus 50mg
30mg

(Source: Centre for Science in the Public Interest www.cspinet.org/new/cafchart.htm, American Beverage Association, 2005, and Journal of Agricultural and Food Chemistry, 2003)
Death by chocolate?

Chocolate’s major active ingredient is cocoa, a significant source of the stimulant theobromine. Research by British psychologist Dr David Benton at the University of Wales in Swansea, showed chocolate to be an excellent mood elevator.36 When he played sad music to a group of students, their mood sank. He then offered them milk chocolate or carob (a natural chocolate substitute that is similar in taste), although they did not know which one they had chosen. The participants found that the chocolate raised their mood, whereas the carob didn’t. Moreover, as their mood fell, their cravings for chocolate increased.
In addition to theobromine – also found in tea and coffee, as we’ve seen – chocolate contains the mood-enhancing stimulant, phenethylamine. Both of these stimulate dopamine production. Even experimental alcohol-loving rats, when given the choice, will replace some of their alcohol intake with chocolate.
The downside of chocolate

Too much chocolate, especially the highly sweetened kind, causes all the problems of going overboard on sugar, including weight gain.
It is often high in the wrong kinds of fats.
The addictive nature of it suggests the development of tolerance, so ‘just one chocolate’ becomes ‘just one more’.
Cocoa beans, like coffee, are grown in countries where pesticide use is unregulated, exposing the consumer to cancer-causing compounds.

However, chocolate does have some redeeming qualities. It is very high in antioxidants. Of all the stimulant vices it’s probably the least bad, provided you eat the pure, dark, preferably organic stuff, not cheap bars full of fat and sugar. Eat chocolate with a minimum of 70 per cent cocoa solids. But, as with any stimulant, if you eat it every day, or find yourself craving it, you’ve gone too far. Keep chocolate as a special treat, not a daily ritual.
Addicted to adrenalin and cortisol

Stress itself is a stimulant, promoting high levels of adrenalin and cortisol, which keeps you alive and alert. Many people get almost addicted to the buzz of adrenalin and have to keep going, fuelled by additional adrenalin and cortisol-related stimulants such as coffee and cigarettes.

Case study KATHY

Kathy was an adrenalin junkie. She was drinking up to 30 cups of coffee a day to keep herself going. She also smoked 10 to 15 cigarettes a day. She was gaining weight and losing sleep. She wasn’t fully awake when she was awake, nor peacefully asleep when she was asleep. Within six weeks of starting our recommended diet, however, plus taking the specific supplements explained in Part 2 (combined in our How to Quit Action Plan), she had given up all caffeine, had stopped smoking, and was feeling loads better. She went to bed at 11pm, instead of 2am, and was waking up feeling refreshed. Three months on she had lost a staggering 20kg (3 stone/44lb) without going hungry. Her energy was greater, her skin looked much clearer and she hadn’t suffered from any colds. ‘I feel so much better. My energy levels are improved, I sleep like a baby, I don’t miss coffee at all and I’m not smoking.’

Nicotine

Alongside caffeine and alcohol, nicotine is one of the three most widely used psychoactive drugs in our society. With no redeeming value ‘smoking will continue as the leading cause of preventable, premature mortality for many years to come’, says the US surgeon-general. According to the World Health Organization nearly 5 million people a year die prematurely as a result of smoking.
Nicotine, the primary stimulant in cigarettes, has a significant effect even in small doses.

If you have ever smoked, can you recall the sensation of your first cigarette? It probably tasted terrible, burned your mouth and lungs (if you actually inhaled), and made you nauseated and dizzy. Those are some of its toxic effects in action. A few more smokes, and for most people the body no longer rebels. In fact you rather like it. In short: you’re hooked.
Nicotine has a complex series of actions, both stimulating and relaxing. For many people it is more addictive than heroin – and is often the hardest addiction to break. It stimulates the adrenals to release adrenalin and cortisol, raising blood pressure and heart rate, and increases gastrointestinal activity. It also acts as a muscle relaxant. (We’ll explore this more in Chapter 21.)
In the brain, nicotine activates the release of dopamine, exhibiting a stimulant effect similar to that of caffeine. It also has a short-term antidepressant effect, although this is most often followed by a rebound depression. In larger amounts, nicotine acts as a sedative, probably because of its effect on serotonin. People trying to kick the tobacco habit describe the accompanying tension and irritability as ‘feeling like you want to jump out of your skin’. They often experience low blood sugar problems, which leads them to overeat and gain weight. The trouble is that smoking keeps your brain’s chemistry hooked in to needing stimulants.

Case study AMANDA

Eleven years ago, after years of drug abuse, Amanda quit heroin, but still felt lousy, with constant low energy, and occasionally got the shakes if she hadn’t eaten. She ‘managed’ her state by smoking up to 40 cigarettes a day, plus caffeinated drinks and sugar or sugary snacks. She often felt anxious and irritable and didn’t sleep well. Within a month of following our recommendations in Part 2 (combined in our How to Quit Action Plan), her energy had rocketed. Twelve weeks later she had quit smoking, avoided caffeinated drinks and sugary foods and definitely felt the benefits. ‘My energy is so much better. I go to bed at 11pm and wake up feeling refreshed. I no longer suffer from mood swings, and I feel much more motivated and less stressed.’ Even after 11 years she was able to ‘rebalance’ her brain’s chemistry in just a few weeks with the right intake of nutrients, both from food and supplements.

The How to Quit programme

Whether you are reading this book because you want to give up caffeine or cigarettes, or have stopped using drugs or drinking alcohol, but still ‘rely’ on stimulants, if you really want to feel great you have to go the whole hog and break out of the sugar-stress-stimulant trap. Just quitting one addictive substance, but continuing others rarely works. You need to eat a diet that balances your blood sugar and take supplements that help ‘reset’ your brain’s chemistry. How to do this is explained in Part 2.
SUMMARY

Nicotine, caffeine and sugar are all stimulants.

The more stimulants you have, the more stressed and tired you become.

Your brain becomes increasingly less sensitive to your own natural stimulants – dopamine, noradrenalin and adrenalin. As a consequence you need more stimulants just to feel normal.

Anyone who has quit an addictive substance but continues to rely on stimulants still has an addicted brain

Are you avoiding pain

2014-05-15T02:39:00.000-07:00

It’s not just the buzz we go for in mood-altering substances, it’s the anaesthetic. If you’ve had a tough week, or a bust-up with a girlfriend or boyfriend, or are dead bored with your career choice or have no idea what direction to go in life, one way to relieve the pain is to get drunk, get stoned or get out of it. It works. Temporarily you forget whatever it was that was eating you up. Using a substance to blot out emotional pain may or may not lead to addiction. But the more you do it, the higher your risk. Although it is very normal to want to escape pain, it’s important to understand why you are using chemical substances to do it – and to find a safer way.
How pain comes and goes

All thoughts and feelings have a corresponding change in your brain’s chemistry. In Chapter 2 we learned about how our brain’s neurochemistry rewards us for certain behaviours with good feelings, by stimulating the release of serotonin, endorphins and dopamine. The opposite is also true. When something happens that makes us feel bad, it sets up a corresponding craving for something to make us feel better and get those pleasurable endorphins flowing. ‘Hugs not drugs’, says an AA slogan, since both do have the power to up our feel-good neurotransmitters.
These are part of the brain’s natural painkillers. The reason why morphine or heroin, for example, kill pain is precisely because they lock into the brain’s receptors for its own natural painkillers – endorphins. They are released, for example, when you are dying. They make you blissfully unconscious of any hassles in life.
The same thing happens, although to a lesser extent, with alcohol, cannabis and tranquillisers. They switch off anxiety, helping you to chill out and temporarily forget about whatever was such a big deal a minute ago.
The longer you go on using the drug, the less pain relief you get, and the more pain you experience the next day as a consequence.

Pain relief becomes more pain

In the short term drugs all ‘work’. They relieve the pain and make you feel good. But soon they bring their own pain – the pain of withdrawal, largely due to endorphin, serotonin and dopamine depletion, leaving you wanting more of the same.
But that’s just the chemistry of it. As a consequence of learning to avoid painful circumstances by ‘numbing out’ with drugs, situations that you need to deal with often get worse, or you make them worse by saying or doing the wrong thing ‘under the influence’.
What are you avoiding?

Apart from this immediate pain, what are you avoiding when you are using drugs?

Are you bored or unfulfilled in your work or relationship?
Are you betraying yourself by not being who you are, or not standing up for what you believe in?
Are you stuck in a rut and need a change, a new challenge to absorb your desire to learn or make a difference?
Have you accumulated so much ‘stuff’ (fears, disappointments, anger, relationship problems)?
Are you imbedded in your negative patterns and negative self-talk? (Self-talk is how we talk to ourselves, in our minds or out loud. Some of our self-talk is encouraging and constructive. Some of it is negative and discouraging. When you are imbedded in your negative self-talk you behave as if it is true whether or not it is.)
Are you drowning in your sorrows?
Is your depression really accumulated anger without enthusiasm (‘Don’t get sad, get mad!’)?
Are you lonely?
Are you searching for something – something that gives meaning to life – in drugs?
Is it time you did some work on yourself and where you are going, rather than numbing out with one substance or another?

This kind of emotional healing – getting the past out of your future – is for many a vital component of breaking an addictive habit. Finding meaning and purpose in life without drugs is a vital key for some people. For this reason it’s part of our 12 Keys to Unaddicting Your Brain, explained in Part 2. We outline a variety of options to explore, from one-to-one counselling to intensive life-changing training courses (see Chapter 18).
AA has a 12-step process towards recovery; step four is to ‘make a searching and fearless moral inventory of ourselves’. If you follow this, you may better understand what it is that makes the use of a particular drug so attractive to you. In Appendix 1 (which is on our website www.how2quit.co.uk) you will see a list of questions. This is designed to help you identify what it is you’re compensating for, and whether there’s a better way to achieve peace or fulfilment than using your drug of choice. The combination of unaddicting your brain with optimum nutrition (as we explain later), and resolving the issues that leave you feeling unfulfilled, is a powerful step away from a pattern of addiction.
Understanding why you use substances

One incredibly useful way of understanding the natural behaviour of wanting to escape pain is the model of the Doors of Compensation®, described by the psychologist and philosopher Oscar Ichazo.
In an article on drug abuse he says,

Drugs (all of them) can be characterised as ‘energy consumers’, consuming energy at a rate much greater than our natural ability to replace it. As drugs burn all our acculated vitality in short periods of time, the brief exaltation is inevitably followed by depletion of vital energy, felt as the ‘down’, the depressant effect of drugs. Nothing can replace a natural, clean body capable of producing natural and clean vital energy.

The order of damaging drugs

Oscar Ichazo rates the drugs most damaging to our vital energy (explained on page 81) in the following order, from most damaging to the least: alcohol, heroin and opiates, tobacco, cocaine, barbiturates, antidepressants, amphetamines, marijuana and caffeine.

How we keep ourselves psychologically in balance

Ichazo’s model describes nine different ways that we dissipate energy. Stimulants and drugs are just one of these. Compensating in one way or another is completely natural and can be seen as the way we attempt to keep ourselves psychologically in balance. Think of your consciousness – your psyche – as a container. When we react to situations with emotional charge (when things don’t go the way we expected, or when we experience stress in one form or another) the pressure on our psyche increases. To release the pressure we compensate by behaving in a particular way – using one or more of the Doors of Compensation. That’s why, for example, people go boozing on a Friday night as an escape from a stressful week, or take their stress out on the family by being bad tempered, or stuff themselves full of food. Each of these is a way of dissipating energy and reducing the psyche’s tension.
The Doors of Compensation

Understanding how we use these doors of compensation helps to identify sources of stress and allows us to develop healthier ways of staying in balance to support a productive and happy life. Ichazo has developed a one-day training session to help you understand how we all use doors of compensation (see Resources, page 486).
The nine Doors of Compensation

1. Toximania The use of toxic substances, including cigarettes, alcohol and cannabis.

2. Psychosomatic illness Being overpreoccupied with one’s mental and physical health and illness.
3. Overexertion, which might manifest as workaholism or excessive sport.
4. Crime Ways of getting even because you didn’t feel you got a fair deal.
5. Phobia, from dislikes to aversions.
6. Panic Always being in a high-anxiety state and then spreading it to others.
7. Debauchery (excess), which could manifest as excessive intake; for example, with food.
8. Cruelty, which includes being mean, using abusive language and behaviour.
9. Sensuality, which includes excessive sex and over-preoccupation with the pleasures of the senses.

The doors and their domains

Each door of compensation relates to a particular domain where a specific psychological imbalance occurs. For example, when we have stress in the work domain we go into panic. Toximania (the excessive use of toxic substances including cigarettes, alcohol and cannabis) is associated with the domain of our sentiments and feelings. So, having the objectivity to notice which ‘doors’ are attractive to you also shows the aspects of your life where you are generating internal pressure.
Whereas we all use these ways of compensating at different times during every day, the degree to which we use them is also significant. The first degree of use is just occasionally, for temporary satisfaction; the second degree is regularly; the third degree habitually to excess. Using drinking as an example:

The first degree is the odd occasion when you have a couple of drinks after a stressful week.
The second degree is when you drink every day and you are anaesthetised by it.
The third degree is when you habitually drink with drunkenness as the outcome, which is debilitating.

By the third stage such behaviour denotes addiction and represents a continual dissipation of energy and consequent brain chemistry imbalances, which are worsened by poor nutrition.
Foods and drinks that dissipate energy

From the point of view of nutrition, the foods and drinks that are associated with dissipating energy, if used regularly or habitually, are sugar, alcohol, coffee and chocolate. To generate and maintain a good level of energy it is best to either avoid these completely, or at least to get to the point where they are an occasional treat and not a daily prop. (An exception is green and black teas, which have many reported health benefits.)
Overeating

Another way of dissipating energy is to eat too much. Indian lore says we should fill our stomachs with one-half food, one-quarter water and leave one-quarter for the prana, or vital energy. In other words, eat to the point where you are satisfied but not full. This has the effect of energising you, whereas overeating has the opposite effect.
Vital energy

Energy isn’t just about the process of eating food and metabolising it with the aid of oxygen from the air you breathe. Theres another factor, called chi in China, ki in Japan and prana in India, which we explain in Chapter 17. It is also called ‘vital energy’ and it can be experienced through certain exercises and meditations. These exercises can leave you feeling alive and energised, with a delicate sense of vitality that can be directly experienced as heat in the palms of the hands, the feet and in the belly.

Deal with the issues first

So, nutritionally, it is best to avoid all the energy consumers and not to overeat. This will certainly give you more energy to deal with the stress in your life. However, from the psychological point of view, these ‘doors’ are used to relieve internal pressure. So by dealing with the issues that generate the psychological pressure, the need to use energy-depleting third-degree doors of compensation becomes less. In other words, you would need to change how you deal with situations in your life as well as changing what you eat and drink. The two go hand in hand.
SUMMARY

Through the depletion of neurotransmitters and unhealthy changes in brain cell membranes, drugs produce ‘morning after’ pain.

Excessive use of drugs often attracts more problems in life and increasing levels of emotional pain.

In serious addiction the drug no longer delivers pleasure but becomes a source of pain.

Identifying the sources of the pain you seek to avoid, releasing accumulated emotional charge, and finding fulfilment without drugs is an important part of the way out of an addictive process, together with optimum nutrition for restoring the brain’s non-addictive chemistry.

All drugs deplete energy.

We often use drugs to release internal pressure or pain, to compensate

Are you ready to quit??

2014-05-11T01:12:00.000-07:00

Whatever it is that you ‘need’ in order to feel good, there’s something that doesn’t feel right about having to consume a certain substance to feel OK. You’ve probably also found that the original kick you got from the substance you use isn’t nearly as good as it used to be. It just doesn’t fill that need any more. You might even have noticed that the substance doesn’t actually make you feel good at all 09 just less bad. The ‘joy’ of the substance has become partly or wholly the fact that it brings relief, however temporary. You might also have found that your relationship with your substance actually causes you problems or gets in the way of your ability to function in the world in one way or another.
What’s your addiction?

Take a look at the list of substances opposite. Ask yourself honestly which of these you consume on a regular basis, either weekly, daily or several times a day (tick the box). Or, if you are reading this because you are concerned about a friend, find out as best you can about what he or she consumes.

Weekly Daily Several times a day
Caffeine
Sugar
Alcohol
Nicotine
Marijuana
Sleeping pills
Tranquillisers
Antidepressants
Painkillers
Stimulants (such as Ritalin)
Cocaine or other stimulant drugs
Heroin
Ecstasy (MDMA)
Other

Now, take the first substance you ticked and ask yourself this simple question: How would you feel if you quit this substance completely for the next fortnight?
If you wouldn’t be able to quit we could say that you are addicted. Another definition of addiction is that you continue to use the substance despite it having harmful consequences – on yourself, your work or your relationships. If you could quit but you know you’d feel rough, we would say that you are dependent.
Now look at the list on page 16 and tick the appropriate column so that you have a record of your relationship with these potentially addictive substances. If, on the other hand, you have already quit one or all of these substances and still feel rough, with low energy, mood swings and a feeling of emptiness, tick the box labelled ‘still suffering’. What you tick is your baseline.

Dependent Addicted Still suffering
Caffeine
Sugar
Alcohol
Nicotine
Marijuana
Sleeping pills
Tranquillisers
Antidepressants
Painkillers
Stimulants (such as Ritalin)
Cocaine or other stimulant drugs
Heroin
Ecstasy
Other

Take a photocopy of this page and have a look at it again when you’ve completed our How to Quit Action Plan (as detailed in Part 4). We hope that there will be no more ticks in these boxes, if that’s what you want. The advice in this book will also help you recover your joie de vivre – a lack of which leads many towards using mind-altering substances in the first place.
Of course, we are not proposing that all of these substances must be avoided by everybody all the time. For most, the occasional coffee, sugary food or alcoholic drink is perfectly OK. Assuming you are not a recovering alcoholic, and if you can occasionally partake without triggering a need to do it over and over or gradually increase the amount you consume, good. If not, then an appropriate goal for you would be to abstain completely from the substance that is a problem for you.
A culture of addiction?

In Britain alone it is estimated that there are over 10 million smokers, and the same number of ex-smokers, whereas six and a half million people drink harmful levels of alcohol. In terms of serious consequences a person dies every month from ‘E’ pills and amphetamines; a person dies every day from heroin or methadone, every 20 minutes from alcohol and every four minutes from the consequences of smoking.
Not only is the use of these potentially addictive substances going up and up, especially in the Westernised countries, but so too is the amount we spend on them daily. Some of us spend as much on these substances as wd-a on food. Why?
The answer, most of the time, is that we think or hold on to the belief that they make us feel better – happier, less stressed, more energised, more ‘connected’, more relaxed or in less pain. The trouble is, the more you have, the more you need (that’s the first criterion of addiction: you become tolerant to its effects), and the more you need the worse you feel when you don’t have it (that’s the second criterion: withdrawal symptoms). Both tolerance and withdrawal happen because these substances change the way your brain’s chemistry works until you end up programmed for craving and addiction.

Why haven’t you quit?

The chances are you’ve tried to give up the substance or cut down many times. In the beginning you thought you could just do it with willpower but, despite having the motivation and will, after a few days or weeks, you were back where you started. Why?
Why, despite all your good intentions, did you start using the substance again when you’d decided to stop completely? It probably doesn’t even make sense to you that if your feel-good substance is no longer giving you the same pleasure it used to, or if it is creating some kind of problems in your life, you choose to keep using it or keep going back to it.
The answer is simple, and one of the main messages of this book:
When you quit, you experience what we call ‘abstinence symptoms’, which may be more difficult for you to tolerate than the problems that result from continuing or going back to your substance of choice.

The other important message of this book is that there is a way out – it is possible to quit and not feel s**t.
Someone may have told you that you might feel lousy for a few days, but then you would feel better. But that didn’t happen for you. And then, did your desire for the substance overpower your desire to quit? Do you feel a failure because you can’t do something you know you should? Despite your desire to quit, is there a niggling voice in your head that says you’ll never succeed? You’ll soon discover, as you continue to read, that what happens to you when you use a mood-altering substance and what happens when you don’t is a result of changes in your brain. The very nature of addictive substances, and the way they reprogramme the instinctive and emotional part of the brain, is a far stronger influence on your behaviour than your rational mind. Unless you reprogramme your brain’s chemistry away from dependency, quitting becomes difficult, if not impossible – and at the very least, certainly uncomfortable. Strong, instinctive and largely unconscious forces – sometimes as strong as the survival instinct itself – are at work to keep you consuming your feel-good substance. But once you understand the dynamics, and how to change them, it gives you power to control these seemingly irresistible cravings.
You are not alone

If you struggle to feel yo, or less bad, without a smoke, something sweet, something to drink, or some other substance, you are not alone. Addiction or dependence affects most of us at one level or another. The use of addictive substances, whether caffeine in tea and coffee, or alcohol and cigarettes, is part of everyday life for most of us. Most people are somewhere along the continuum from mildly dependent to seriously addicted.
Many of us use a combination of substances to change how we feel: sugar, alcohol, nicotine, caffeine or prescription drugs (to name the legal ones). We harshly judge the use of illegal drugs, such as cannabis, cocaine, amphetamines, heroin and Ecstasy, but your brain doesn’t care whether a substance is legal or not. All of these substances contribute to scrambling your brain’s chemistry.
The addiction epidemic

In Britain, despite all the campaigns, taxes and over 100,000 smoking-related deaths each year, one quarter of all adults smoke.1 We drink an average of 16 units of alcohol a week – that’s 4.5 litres (8 pints) of beer.2 A third of 16 to 24 year olds smoke and their average alcohol intake is 18 units a week – more than two bottles of wine. Collectively we drink 70 million cups of coffee every day – the equivalent of two each for adults.3 One-quarter of our water intake is from caffeinated tea.4 In one survey of over 5,000 people, the average caffeine intake per day was 241mg (a regular coffee or strong tea is about 100mg).5 Most of us are having at least three stimulant drinks a day. And some of us are drinking a few cups more to make up for those who don’t drink any.
An estimated 7.5 million people in the UK have used cannabis, and up to 2 million do so on a regular basis.6 One in ten of the UK population use one or more illicit drugs.7 In the UK the number using cocaine has doubled in the last five years to over 1 million people.8
In America 22 million people are classified with substance abuse or dependence problems.9 Seven million children in the US take stimulant drugs (usually for attention or hyperactivity problems) – that’s roughly one in five.10 In Britain 359,000 prescriptions were written out for just two (Ritalin and Concerta) in 2004.11 In the UK there’s an estimated 1.7 million tranquilliser addicts (that’s benzodiazepines alone) and 31 million antidepressant prescriptions written annually. The number of people addicted to them is unknown. Over 180,000 people seek addiction treatment each year.12
ESTIMATED NUMBER OF PEOPLE DEPENDENT/ADDICTED
(per cent of UK population)

Nicotine 15 million (25%)
Caffeine 12 million (20%)
Alcohol 4.6lion (8%)
Tranquillisers 1.5 million (2.5%)
Heroin 150,000 (0.25%)
Cocaine 20,000 (0.03%)

(Sources: Ash, Drug Scope, Alcohol Concern, Department of Health, NHS)
But am I addicted?

Addiction to any substance is a serious problem. Perhaps you think because you do not consume illegal drugs or are not an alcoholic that you are not addicted or that your heavy use of nicotine, caffeine or sugar is not a problem. The proof is in the pudding: if you’ve tried to kick the habit but ended up feeling so bad you start using the substance again, then you’re probably addicted. The longer you’re addicted the more your brain’s chemistry changes, the less effective the substance becomes and the stronger your desire grows to keep using it. It’s a vicious circle.
Abstinence symptoms: why quitting is so hard

As we have said, there are symptoms of addiction that occur while you are using a substance, but even more distressing for most people are those that occur when they stop using the substance. We have already explained a little about these symptoms and that we refer to them as abstinence symptoms. These can vary from mild to extremely severe, and they are the reason that most people fail to stick with their attempts to quit.
Acute withdrawal: symptoms when you first stop

The first symptoms that occur when you quit a substance are related to acute withdrawal, and in most cases are the opposite of the effects of the substance. For example, if you are using a substance that stimulates you, when you stop you will feel a lack of energy: lethargy, drowsiness, fatigue. If, on the other hand, you have been using a substance that relaxes you, when you stop you will probably feel a high level of agitation, anxiety and jitteriness. Some substances, like nicotine, do both, and quitting brings on a mixture of withdrawal effects. (If you have a severe addiction to a drug with relaxing effects – such as alcohol, a painkiller or an anti-anxiety drug – it may not be safe to stop taking it suddenly and we would strongly recommend that you get medical support.)
Most of the acute withdrawal symptoms will subside within three to ten days. And most people can make it through those, expecting that then the worst is over and they are in the clear. However, what happens next is that other symptoms will begin to emerge, lasting weeks, months or even years if you don’t know what to do to reduce or eliminate them. Some of these may actually become worse over time. The most common ones are listed in our Scale of Abstinence Symptoms Severity on page 26. But before you look at it we will describe in some detail a few of the symptoms that tend to be the most baffling and distressing over time. In Part 2 we’ll show you how to quit without experiencing these symptoms.
Hypersensitivity: when everything is too much

One of the most common abstinence symptoms is hypersensitivity to everything. Put simply, you have heightened sensitivity to external and internal stimuli: noise, light, touch, pain and stress. People who experience this most intensely are unable to filter out background noises and happenings, and this causes them to feel bombarded by all that is going on around them. If you are troubled by this, you feel constantly overwhelmed by everything going on around you and by all your internal thoughts and feelings. What would usually be considered mild stress becomes major stress. Sounds that others do not notice become major distractions for you. Pain is more intense, and simply being touched can even sometimes feel like being mauled. People who are the most troubled by this feel overwhelmed by a world that comes at them full force.
In most cases this particular symptom is partly genetic. Alcoholics, children of alcoholics and those with attention deficit hyperactivity disorder (ADHD) have been found to ‘magnify perceptual input’ (magnify everything their senses experience) and this has been associated with craving for a mood-altering substance.13 It commonly exists prior to using an addictive substance and probably contributes to the risk that someone will use mood-altering substances at an early age. For some, certain substances, including alcohol, make this symptom disappear. So it would be expected that people plagued by it from childhood would use a substance that offers relief and that they would experience it again when they quit.
You find it difficult to concentrate

Although the inability to concentrate can result from any number of brain disturbances when you quit a substance, it can also be, and often is, related to hypersensitivity. When the buzzing of a fly demands as much attention as the person talking to you, it is difficult to stay focused on what that person is saying. It’s not rudeness and it’s not intentional. It is just very difficult to maintain a focus when everything around you is calling to you at the same time. It can be frustrating and embarrassing to realise that someone is talking to you but you haven’t taken it in.
Your memory becomes poor

Problems with memory result from the inability to concentrate. If you didn’t take in what someone said to you or were distracted when it occurred, you won’t remember it. Or the memory will be sketchy. You can’t recall what was never really recorded in your brain in the first place. Memory problems can also be related to fuzzy thinking, which often occurs when neurotransmitters in the brain are not communicating properly (we explain how neurotransmitters work in Chapter 2). It is hard to remember what you haven’t grasped in the first place.
Your mood changes

You may experience anxiety, depression or both as a result of quitting. A certain amount of psychological stress is expected when change is going on. Change is stressful, and it is normal to have some fear connected with quitting your feel-good substance. But stress is exacerbated to the point of anxiety by hypersensitivity and the inability to concentrate and remember.
Maybe what you feel is not what you would really call depression, but is just a general feeling of discomfort or unpleasantness, an inability to feel pleasure. You feel that the colour has gone out of life. Sometimes these feelings come and go and take the form of mood swings. One day you feel good and then soon feel very ‘down’. The tendency is to believe when you’re feeling good that you are always going to feel good; it’s then disheartening when you are again overcome by the inability to feel pleasure.
You crave substances to change your mood

Intense cravings, or what some refer to as ‘drug hunger’, is a powerful compulsion to alter one’s mood with a substance. The abstinent person experiencing cravings knows what will bring relief. Hypersensitivity has been linked to a strong craving for alcohol, drugs and sweets. And alcohol, drugs and sweets normalise it. Feeling incomplete or inadequate or unfulfilled is common with abstinence from any substance that you have used to satisfy you. You experience a feeling of emptiness and a yearning for something, anything, to fill up the emptiness.
You have trouble sleeping

Many people experience sleep problems when they quit addictive substances. A common problem for abstinent alcoholics in early recovery, for example, is unusual or disturbing dreams. This is probably because alcohol suppresses REM sleep. This is the stage of sleep when we dream. And when we miss REM sleep our body tries to make up for it when we do begin to get dream sleep. The same is true with cannabis. This results in a rebound effect and we dream more than normal.
People who quit using other substances have other problems, such as having trouble getting to sleep and/or staying asleep. If this happens to you, you will probably feel sleepy in the daytime or feel tired all the time. Some people experience a difference in their sleep patterns, sleeping for long periods of time or sleeping at different times of the day.
The most serious sleep problems are associated with withdrawal from sleeping pills or benzodiazepines (like Valium and especially Xanex or Klonopin).
CAUTION It is dangerous to come off these drugs suddenly; you should taper off gradually. If you withdraw too rapidly, you may go for long periods without sleeping at all or worse, slip into a coma and die. For this reason we strongly recommend that you seek experienced medical help when tapering off any benzodiazepine.
Record your symptoms to monitor your recovery

Take a look at the Scale of Abstinence Symptoms Severity on the following pages. These are the most common symptoms that people experience when they quit and their brain chemistry is still in dependency mode. Even if you quit something months or even years ago your brain may still be out of balance and you may continue to experience some of these symptoms. Of course, not everyone who quits suffers from all these symptoms. What symptoms you have and how severe they are depends partly on what drug you have used and partly on your own biochemistry. Although we talk about these as ‘abstinence’ symptoms, sometimes it’s these kinds of symptoms that lead you to use a substance in the first place to provide relief. Your brain chemistry can lilly be out of balance from birth.
Here are some guidelines for getting and evaluating your abstinence severity score:
1. Use the scale to find your score when you have quit, because if you are still using your feel-good substance, your score will not give you the correct picture. This is because the substance is changing how you feel. The question is how you feel when you are not using it. So, use the checklist to determine your score after you have not used your substance(s) for at least one day.
2. If you are going through a medical detox for alcohol or other drug withdrawal, find your score when you are through the acute withdrawal phase.
3. Circle the number that best indicates the severity of each symptom you are experiencing today while you are no longer using your mood-altering substance.
SCALE OF ABSTINENCE SYMPTOMS SEVERITY

Circle the number that best indicates the severity of each symptom you are experiencing today (zero indicates the absence of the symptom, 10 represents an extreme, intolerable intensity level). Answer each question as honestly as possible.

Low level High level
Craving or drug hunger 0 1 2 3 4 5 6 7 8 9 10
Craving for sweets/sugar/bread 0 1 2 3 4 5 6 7 8 9 10
Craving for salt 0 1 2 3 4 5 6 7 8 9 10
Loss of appetite 0 1 2 3 4 5 6 7 8 9 10
Overeating/always hungry 0 1 2 3 4 5 6 7 8 9 10
Bloating or sleepiness after eating 0 1 2 3 4 5 6 7 8 9 10
Sense of emptiness/incompleteness 0 1 2 3 4 5 6 7 8 9 10
Anxiety 0 1 2 3 4 5 6 7 8 9 10
Internal shakiness 0 1 2 3 4 5 6 7 8 9 10
Restlessness 0 1 2 3 4 5 6 7 8 9 10
Impulsiveness/acting before thinking 0 1 2 3 4 5 6 7 8 9 10
Difficulty concentrating/focusing 0 1 2 3 4 5 6 7 8 9 10
Fuzzy thinking/head cloudy/ brain fog 0 1 2 3 4 5 6 7 8 9 10
Memory problems/memory loss 0 1 2 3 4 5 6 7 8 9 10
Depression 0 1 2 3 4 5 6 7 8 9 10
Mood swings 0 1 2 3 4 5 6 7 8 9 10
Negative self-talk 0 1 2 3 4 5 6 7 8 9 10
Irritability/impatience with people 0 1 2 3 4 5 6 7 8 9 10
Daytime sleepiness/drowsiness/ dozing off 0 1 2 3 4 5 6 8 9 10
Problems getting to or staying asleep 0 1 2 3 4 5 6 7 8 9 10
Fatigue/lack of energy/worn out 0 1 2 3 4 5 6 7 8 9 10
Hypersensitivity to stress 0 1 2 3 4 5 6 7 8 9 10
Hypersensitivity to sound or noise 0 1 2 3 4 5 6 7 8 9 10
Hypersensitivity to pain 0 1 2 3 4 5 6 7 8 9 10
Dry mouth/dry eyes/dry skin 0 1 2 3 4 5 6 7 8 9 10
Aches/muscle or joint pain/ headaches 0 1 2 3 4 5 6 7 8 9 10
Add up your total score:

When did you first experience the symptoms?

Although we call these ‘abstinence symptoms’, you may have had some of them before you got hooked. Perhaps the substance you became addicted to was the one that worked best to relieve those symptoms. In other words, the symptoms can be the reason you began using the substance in the first place, or they can be the consequence of substance overuse. Which way is it for you? If it is that the symptoms existed before and you used a feel-good substance to relieve them, then they will return even more intensely when you stop using that substance, depending on the degree of damage to your nervous system caused by the substance.
Whether the symptoms are cause or effect, if you have quite a few of these symptoms when you attempt to clean up your act, it’s time to do something about it. If you are still unsure whether or not you are ready, ask yourself this:
Would you be ready to quit if you knew you didn’t have to go through the discomfort you experienced when you tried to quit in the past?

See how your symptoms improve

Most people who follow our programme cut their abstinence symptom score by at least a third within one week, and by a half to three-quarters within four weeks simply by tuning up their brain chemistry with our How to Quit programme. And that’s the big secret to quitting successfully: creating a level of health and a state of mind free from craving and discomfort.
Are you still unsure if you are really addicted?

Many people tell us that they consume substances on a regular basis, get great joy or satisfaction from doing so, and therefore can’t be addicted or dependent. Well, that would depend upon your definition of addiction. As we have been pointing out, addiction is not just about what happens when you use a substance, but what happens when you don’t. When we talk about addiction or dependency in this book we are talking about a condition in which there is a compulsion to keep using a substance despite negative consequences, as well as withdrawal symptoms when regular use ceases.
Of course, you can have negative consequences with or without compulsive use and withdrawal symptoms. The substances we are focusing on are harmful in a number of ways even if we are not addicted to them. Many people who are not addicted drink more than they should and may sometimes drink irresponsibly. Caffeine and sugar in excess are not good for us whether or not we are addicted. The big question is whether or not you can easily give them up when it becomes apparent that it is wise to do so.

Case study SARAH AND KENNY

Let’s take two people who enjoy sweets and eat them on a regular basis. They both begin to gain weight and to have some health problems. They both decide to lose weight. Sarah, who is not addicted, is able to reduce or perhaps eliminate sweets from her diet. She loses weight and enjoys the accomplishment of controlling the amount of sugar she consumes. Kenny stops eating sweets only briefly before going back again and again to the same pattern of eating. He gradually increases the amount he eats and ultimately develops diabetes. Despite his weight and physical problems he is unable to control his sugar intake. He is addicted to sugar.

Most people feel tired and stressed as a consequence of too much sugar, caffeine, alcohol or cigarettes. Yet the addicted brain says ‘have a coffee/have a drink/have something sweet/have a cigarette – it will make you feel good.’ If you recognise that these substances are harming you and you can make the choice to stop using them without craving and discomfort – or if you are able to limit them to occasional use (not likely in the case of cigarettes) – you are probably not addicted. But if you continue to consume the substance despite ongoing negative consequences, and if you feel lousy when you quit, you are addicted and need to do something about it.
You can let go

If you are ready to quit, we have a How to Quit programme to help you. In most cases this takes 12 weeks to complete – defined as being free from abstinence symptoms. We will show you how to free yourself from the hold your substance of choice has on you. If you are not sure whether you are ready to give it up, come along with us. Find out what can happen if you choose to quit. We will show you that it really is possible to quit without feeling s**t, with this amazingly successful, scientifically based programme.
SUMMARY

If you are dependent on a substance – caffeine, sugar, nicotine, alcohol, or prescription or illicit drugs – you are not alone. Most of us have some type of dependency.

You may have given up using the substance you are dependent on but suffer from a variety of symptoms we call abstinence symptoms – listed in the Scale of Abstinence Symptoms Severity.

You may have had some of your symptoms before you started using an addictive substance and then found that the substance relieved them.

Whether the symptoms are a cause or a result of using the substance, if you have a number of them, or if the ones you have are very severe, you can do something about them.

The How to Quit programme we describe in Part 4 will help free you from the discomfort of abstinence and prevent you returning to addictive use

The prescription drugs not the answer

2014-05-08T05:55:00.002-07:00

Some of the most widely prescribed drugs are antidepressants, tranquillisers, sleeping pills and stimulant drugs. You might have been prescribed these drugs because you were feeling depressed, anxious or unable to sleep – and then became addicted to them. Or you might have started taking these drugs to help you deal with the withdrawal effects associated with coming off another addictive substance. But using an addictive substance to relieve the pain of getting off an addictive substance is not the ansr.
It is true that when most people give up using a feel-good substance because it is creating problems for them, they quickly find another substance to relieve the discomfort of abstinence. When alcoholics stop drinking they increase their intake of nicotine, caffeine and sugar. People who give up smoking frequently relieve their stress by eating – usually junk food. In order to control their weight, some sugar addicts take up smoking. Some marijuana users start drinking or increase their alcohol consumption.
Switching one addictive substance for another is not the answer; it is part of the problem. Swapping one drug for another doesn’t unscramble your brain.

The rise of prescription drugs

In recent years, medical professionals have become part of this problem: by prescribing prescription drugs to relieve the pain of abstinence symptoms. Of course they are not aware that this is what they are doing. They believe they are prescribing drugs for depression, or anxiety, or sleeplessness or lack of energy. And frequently the outcome for the patient is trading one addiction for another. Most of these prescribed drugs are addictive, sometimes more so than the original addictive substance.
While these drug approaches may be a short-term stepping stone to staying clean or sober, the need for alternative stimulants or relaxants is a sure sign that your brain chemistry is still out of balance. Substituting one drug for another doesn’t correct the underlying imbalance. Until this fundamental factor is addressed, any approach to quitting any addictive substance, from cigarettes to cocaine, becomes several times harder.
The main point of giving these prescription drugs is to minimise, in the short term, abstinence symptoms. However, as you will see, if these abstinence symptoms can be more effectively reduced by our nutritional approach (using nutrients and amino acids), the need for substitute medications, with their own withdrawal effects, becomes unnecessary, thus removing this curious paradox: using a drug to correct a biochemical imbalance in the brain caused by using a drug.
How mental-health conditions are diagnosed

You might think that a scientific approach would be to check whether a person actually has a biochemical imbalance, and, if so, exactly which neurotransmitters (see Chapter 2) were low. The correct amino acids or other nutrients could then be prescribed to help restore the brain’s chemical balance. But that is not what happens. Instead, the diagnosis of almost all mental-health conditions, addiction being one, is based solely on a checklist of symptoms that doesn’t tell you anything about what is going on with the brain or its chemistry.
Checking neurotransmitter balance

At the Brain Bio Centre, our outpatient treatment centre, one of the first things we check for in anyone experiencing problems with depression, anxiety or sleep is the balance of neurotransmitters. We do this based on the tests first developed by ProfessTapan Audhya, from New York University Medical Center, who found very low levels of serotonin in the blood of depressed patients.37 Noradrenalin levels are also often low in those with depression.
Knowing that this neurotransmitter is made directly from amino acids found in food, Audhya then gave his patients 5-hydroxytryptophan (5-HTP), the amino acid that’s a direct precursor to serotonin. This corrected the deficiency and resulted in major and rapid relief from depression.
The usual route with prescribing

We’re sure you would agree that the above is a logical approach: to identify the imbalance, then provide the brain with the nutrients necessary to allow it to rebalance. But this is not what happens in most medical practices or recovery centres. When the abstinence symptoms (depression, anxiety, insomnia) are severe, many people are given more drugs (antidepressants, tranquillisers and sleeping pills) that compound the problem. Many addicts then get hooked on these. Heroin addicts are given methadone, and then get hooked on that. For many, it’s harder to get off methadone than heroin, and incredibly difficult to get off certain tranquillisers and antidepressants.
In our experience, some of the new drugs on the market, which were launched on the premise that they were less addictive or had fewer side effects, have proven to be just as bad, if not worse. Let’s take a look at these, starting with antidepressants.
Are you addicted to antidepressants?

Depression is an extremely common symptom in those with addiction problems, especially among alcoholics, both while drinking and when sober. One in six people in Britain between the ages of 25 and 44 suffers from depression, according to a report by the Royal College of Psychiatrists.38 If you are, or have been, one of these people, the chances are you will have been offered antidepressant drugs. If you’ve taken them, the chances are you’ll have a hard time getting off them, especially if you are taking one of the more recent generations of drugs.
Understanding antidepressants

Back in the 1980s the most prescribed drugs were called ‘tricyclic’ antidepressants, the most popular being amitriptyline. In the 1990s these were largely replaced by a new class of drug (with new patents affording them higher prices) called SSRI (which stands for selective serotonin reuptake inhibitor) antidepressants, with names like Prozac, Seroxat and Lustral, and SNRI (which stands for serotonin and noradrenalin reuptake inhibitor) antidepressants, like Cymbalta and Efexor. The marketing of these drugs suggested they were safer and more effective. The so-called ‘cessation effects’ (symptoms experienced when you stop taking the drugs) were downplayed until, in 2003, the Medicines and Healthcare Products Regulatory Agency (MHRA) said that these should be called ‘withdrawal’ effects. (In the US, these are euphemistically called ‘discontinuation’ effects.) SSRIs and SNRIs have largely replaced tricyclic antidepressants, although a review of the research in 2005 noted that most studies show little difference in effectiveness.39
SSRIs and SNRIs are more ‘selective’ in the sense that, in the case of SSRIs they only target the enzyme that clears away serotonin, the key mood neurotransmitter; and in the case of SNRIs, they target enzymes that clear both serotonin and noradrenalin. Their major advantage was supposed to be fewer side effects, and it is not as easy to overdose on them as on tricyclics. The most commonly prescribed SSRIs are fluoxetine (Prozac), paroxetine (Seroxat) and sertraline (Lustral, Zoloft); and the most commonly prescribed SNRIs include venlafaxine (Efexor) and duloxetine (Cymbalta). However, they appear, in some ways, to be more dangerous. We have heard of many patients who have failed to quit Efexor because the ‘discontinuation’ effects are so severe.
The side effects

The risk of suicide in both children and adults for many of these SSRIs is, at least, doubled. A major review in the British Medical Journal of 702 studies on SSRI antidepressants showed that people taking an SSRI were more than twice as likely to attempt suicide compared with those taking a dummy pill.40 The researchers also noted that the actual number of suicide attempts is likely to be much higher, because many of the studies did not gather information on suicide. SSRIs can also cause patients to feel ‘fuzzy’ and can cause major sexual dysfunction, resulting in an inability to climax in both men and women. This can prevent the intimacy that might help someone come through depression and addiction. On top of this, research published in 2006 suggests that SSRIs might dramatically increase the risk of death in those with cardiovascular disease.41 Despite these risks, UK doctors wrote out 31 million prescriptions for antidepressants in 2006, at a cost of £291 million.
All these drugs have side effects, such as nausea, headaches, insomnia, sleepiness, dry mouth, dizziness, constipation, weakness, sweating, nervousness and sexual dysfunction. Many people also report memory loss with continued use. But most worrying are the withdrawal symptoms when you need or want to stop taking them. Consider the case of Nancy:

Case study NANCY

‘When I came to treatment 15 months ago I had been on Seroxat for ten years, clonazepan and Adderall for five years each, and smoking marijuana for ten years. Of all the drugs I was coming off, the antidepressant Seroxat had by far the worst withdrawal problems. I had been taking it for so long that my body did not know what to do without it. I experienced severe withdrawal effects such as panic attacks, the feeling of crawling out of my skin, brain zaps, nausea, dizziness and restlessness, as well as uncontrollable emotions (laughter and crying). I tried to stop taking it all at once and my body could not handle it, so Dr Braly and I decided I would taper slowly off it. The thing that helped me the most was taking the amino acids GABA and tryptophan during the day as needed to ease my anxiety and panic.
‘I truly believe that your approach to treating addiction disease is the best out there. I definitely feel that I would not have been able to successfully come off drugs had I not gone through this programme. I’m extremely grateful to have come off the drugs I was on and especially to have given up Seroxatbeefeel great today and I know it’s a result of the treatment I had and my continuing to eat the right foods and take supplements (especially eating fish and taking fish oil supplements), as well as exercising.’

Taking it slowly

In our experience, supported by scientific literature, antidepressants like Seroxat and Efexor are very difficult to come off. It is essential to taper off these drugs slowly, over at least three months, but, for some people, withdrawal symptoms continue for much longer.42 The organisation CITA (see Resources page 484 for details) gives precise, day-by-day, withdrawal charts for all antidepressants and tranquillisers. If you are on an antidepressant and have tried and failed to come off, Chapter 24 explains how to minimise withdrawal symptoms if you want to quit. But don’t try to get off an antidepressant suddenly and do not make any changes in your antidepressant medication without consulting and cooperating with your, hopefully, nutritionally informed doctor.
If you are taking more than one prescription drug it is very important to withdraw them one at a time, with a gap of ideally three months between them.

Benzos, the Zs and the frying pan

If you’ve been consuming large amounts of stimulants – caffeine, nicotine, amphetamines or cocaine – and you stop, it’s often hard to stay awake when you’re awake or asleep when you’re asleep. You might find yourself drinking more alcohol to help you relax and sleep. When you stop drinking you find it hard to switch off the anxiety and go to sleep. As a consequence you may have either been prescribed some kind of sleeping pill or tranquilliser. You are not alone. In the UK over 16 million prescriptions for what are called hypnotic (sleeping) and anxiolytic (anxiety-reducing) drugs were written out in 2004, at a cost of £37 million.
Remember the Rolling Stones’ song ‘Mother’s Little Helper’? Back in the 1960s the new miracle drugs for curing anxiety and insomnia were the benzodiazepines (the Little Helper’ referred to in the song), said to be safer and less addictive than their predecessor, the ‘non-addictive’ meprobamate (Miltown), which was later shown to be as addictive as the old drugs it had replaced. We now know that the replacement ‘benzo’ drugs are among the most addictive, and hard to get off, substances – for many people, harder than heroin.
The benzos

Benzodiazepines include diazepam (Valium), chlordiazepoxide (Librium), clonazepam (Klonopin) and then the shorter-acting alprazolam (Xanax), lorazepam (Ativan) and temazepam. In the UK, 16 million prescriptions are still written annually for these so-called ‘minor tranquillisers’ to treat anxiety, insomnia, seizures and muscle spasms. Their calming effect is due to their action on GABA: by increasing GABA receptors, the most common receptors in the brain. The benzodiazepines dull both awareness and overall brain activity. However, they also have turned out to be nearly as addictive as what they replaced. Addiction to Xanax has been reported to occur in some people in as little as three days. And, in our experience, benzodiazepines may be the most difficult drugs to withdraw from, sometimes taking months.
CAUTION You should never stop taking benzodiazepines suddenly. It is dangerous. Give yourself plenty of time to taper them off gradually.
The Zs

Then (as the patents and consequently the profits run out) along come the Zs, with names such as zolpidem (Ambien), zaleplon (Sonata) and zopiclone (Zimovane). They were introduced in the 1990s amid claims that they were a safe and non-addictive alternative to earlier drugs. Guess what? They too are every bit as addictive.
A major review in 2005 by the National Institute for Clinical Excellence (NICE) concluded that ‘there was no consistent difference between the two types of drug [benzodiazepines and Zs] for either effectiveness or safety.’43 They too can cause tolerance and withdrawal. Dependence can develop after as little as one week of continuous use. Similarly, you are also advised not to take nonbenzodiazepines for more than a few weeks at most. A bulletin regarding the drug zopiclone advises:

This medicine is generally only suitable for short-term use. If it is used for long periods or in high doses, tolerance to and dependence upon the medicine may develop, and withdrawal symptoms may occur if treatment is stopped suddenly. For this reason, treatment with this medicine should usually be stopped gradually, following the instructions given by your doctor, in order to avoid withdrawal symptoms such as rebound insomnia or anxiety, confusion, sweating, tremor, loss of appetite, irritability or convulsions.44

But these are the sleeping pills you are more likely to be offered on prescription these days, especially if you can’t sleep because you’ve stopped smoking or drinking or you have come off a stimulant drug. In 2004, there were close to 4 million prescriptions made for Zimovane (zopiclone) in the UK alone. They will certainly help if you have a short-term problem with sleeping due to a crisis, but in the long term they are not what’s needed. ‘If you have chronic insomnia,’ says Professor Jim Horne of Lough-borough University’s Sleep Research Centre, ‘it’s because you have an underlying problem and just getting an extra half an hour’s sleep, which is about all the drugs give you, is not going to help tackle it.’
Nutrition can create an escape route

Both benzodiazepines and the Zs can be very difficult to come off, and near impossible without the nutritional support we recommend in Chapter 23. In that chapter you’ll find the story of Pauline, who was hooked on Zimovane: ‘I tried so many times to come off it and failed. Once I didn’t have any for three days, couldn’t sleep and drove into the back of a car!’ Pauline finally got free using our nutrition-based approach. ‘To this day I still take these nutrients and I feel great. Goodbye Zimovane!’
We don’t recommend zepines and the Zs, except for very short-term use. It’s a case of out of the frying pan into the fire. Of course, there are newer drugs now on offer, which are claimed to be non-addictive, although this remains to be seen. First in the ring was eszopiclone (Lunesta), licensed in 2005 for long-term use after studies apparently showed no addiction and no need for an increased dose after six months. It is a variation on zopiclone and is little different in effect. In controlled trials, this drug increased the amount of sleep time by between 15 and 21.5 minutes, compared to a placebo. So why risk potential addiction for so little benefit? In the US you can barely turn on the television without seeing ads for drugs such as these vying for the market of an estimated 1.7 million benzo addicts and probably just as many Z addicts. We don’t recommend you join them. If you have already, or you are tempted to because of abstinence symptoms from other substances, the 12 Keys to Unaddicting Your Brain in Part 2 will dramatically reduce your need. If you have already developed a dependency, also read Chapter 23 to find out the most effective ways to get off these drugs.
Methadone madness

Finally, a word on methadone. Many treatment approaches for heroin addiction involve replacing the heroin with methadone, a similar drug that can be, and is, prescribed to the hundreds of thousands of methadone addicts in the UK alone. If your thinking is that heroin addiction is ‘incurable’ and your goal is to keep an addict away from crime and dodgy needles, then switching to a prescribable, controllable substance may sound like a good thing. But if the ultimate goal is to get clean, methadone is not the answer. A methadone user is still addicted. And methadone is usually harder to get off than heroin. Neither the quadrupling of methadone prescriptions in Britain between 1982 and 1992, nor the doubling of them in the US between 1999 and 2001, has had any effect on the scale of the problem of opiate addiction. Many addicts become addicted to both heroin and methadone. Substantial numbers of people are killed by methadone. Between 1993 and 2004 there were 7,072 deaths involving heroin or morphine and 3,298 deaths involving methadone.45 Currently, about 1.5 million prescriptions for methadone are written every year.46 Some doctors recommend switching to other opioid drugs such as buphenorphine, but these carry the same kind, although possibly not the same scale, of risks.47
In Chapter 27 we look at the most effective ways to get off heroin or methadone or any opioid drug for good.
None of these drugs correct the underlying imbalances that lead to addiction and dependence even though they can temporarily relieve the abstinence symptoms. Even if they do get you out of the fire, you’re still in the frying pan.
The way forward

In the next part we explain the 12 Keys to UnaddictingYour Brain, many of which, on their own, have already been shown to be more effective than prescription drugs and, in combination, are substantially more effective without any of the associated risks of addiction and side effects. There is also nothing to stop you doing these keys to recovery while you are still on a prescription drug. And as you start to feel better, duss with your doctor gradually tapering off the drug as it becomes increasingly unnecessary. How to do this is explained for each kind of drug in Part 3.
SUMMARY

Drugs prescribed for depression, anxiety and sleeplessness are usually highly addictive.

These drugs are often prescribed when people are experiencing abstinence symptoms.

Swapping one addictive drug for another – even if prescribed by a doctor – is not an answer.

It is very important to taper off any prescription drug under the supervision of a doctor.

You can begin using the keys to unaddicting your brain listed in the next section while you are tapering off prescription drugs

How your brain feel good

2014-05-08T05:51:00.000-07:00

As we explained in the Introduction, beating addiction naturally is all about ‘resetting’ your brain away from addiction. In the last few years scientists have made enormous strides in understanding what the biological roots of addiction are and how addictive substances hijack our brain’s chemistry until we literally feel our survival is dependent on them.

Most of the scientific research into helping with addictions is being used to find ways of developing a suitable, and profitable, drug fix for what is often a drug problem. However, this kind of approach creates yet more abstinence problems. Some people move from alcohol to sleeping pills, from cocaine to antidepressants, or from heroin to methadone, but each of these prescribed drugs has its problems, including the problem of addiction.

This chapter explains how, when your brain is functioning as nature intends, it provides you with good feelings. We describe how our How to Quit programme works naturally with the brain’s inherent design, rather than using more drugs to give us ‘quick fixes’ (with yet more abstinence problems). The most important point to understand is that your cravings are created by your body and brain to get you to do the things that temporarily restore balance. When you get the relief provided by the substance, and feel good, this is your brain rewarding you. We are going to show you how you can make your brain reward you, that is make you feel good, without the need for addictive substances. What makes our How to Quit programme so different is that it uses this new understanding of the chemistry underlying addiction to help your brain and body to heal itself naturally. This is achieved by providing the very nutrients that our brains need to make its own feel-good chemicals – the ones addictive substances mimic.

The amazing brain

Your brain is incredible – a mere 1.3kg (3lb) in weight, and mainly composed of fat, it has the capacity to hold trillions of memories. It allows you to experience the delights of eating, the beauty of music, the ecstasy of love, the thrills of sex, and, for some of us, the bliss of inner peace.

It’s also the abode of fear, anxiety, depression and craving. Understanding how this phenomenon works will show you why coffee, cigarettes, alcohol and other drugs produce the effects that they do. The key to the pleasant, even euphoric, effects of mood-altering substances is how they mimic the action of special chemicals in the brain called neurotransmitters. This is described in Chapter 3, but first we’ll explain how the brain makes us feel good – a process that also involves neurotransmitters, the chemical messengers of thought, mood and motivation.

Neurotransmission: getting the message across

You and I communicate with words. The brain communicates with neurotransmitters manufactured in factories in the brain called neurons. Neurons, the principal working units of the brain, are tiny, complex nerve cells that send and receive messages about conditions inside and outside the body. They also serve as mood-control centres that determine the nature and intensity of our feelings and as action centres that largely control our behaviour.

Neurons are scattered throughout the body, but they are most highly concentrated in the brain, followed by the gut (more on this later). They form the ‘road map’ of our nervous system, and there are trillions of them. Neurons connect to one another via branches called dendrites. The average neuron will make 10,000 connections to other neurons, all linking together like a mass of interconnecting highways.

Delivering the messages

Neurotransmitters are the couriers on these highways, delivering messages from one neuron to the next. When the neuron is stimulated by something we hear, see, touch, smell, taste, think, feel or perceive, it releases some of its neurotransmitters. To get from one neuron to the next on the highway, neurotransmitters have to cross small gaps called synapses. The ‘sending’ neuron produces the chemical neurotransmitter, propelling it toward the ‘receiving’ neuron, which has a ‘receptor site’ to receive it. Thera slight complication though. The neurotransmitter is like a letter that only fits into a certain letterbox. If the neurotransmitter does not fit, it is not received by the receptor site. If it does, the message is delivered – that is, the receptor is activated. An electrical signal then travels along the dendrites until it reaches the next synapse, where it triggers the release of more neurotransmitters.

How this makes us feel good

The actions of neurotransmitters play a significant role in feelings of pleasure and well-being. They mediate mood, emotions, thought, motivation and memory. When neurotransmitters are present in optimal amounts, we feel good, we feel satisfied.

Neurotransmitters work together to create feelings of pleasure to reward us for behaviours that keep us alive and comfortable.

The goal of this whole process is to reward us for doing what will keep us alive and functioning well. What produces these rewards is different for different people. Chocolate may produce more reward for one person whereas crisps may produce more reward for someone else; reading an interesting book may be rewarding for one person, whereas skiing may produce more reward for another. We all differ in what gives us satisfaction and in the depth of satisfaction we experience; but we are all motivated by chemical actions in the brain that nature uses to keep us alive, motivated, fully functioning and reproducing by rewarding us with good feelings.

We need feelings of pleasure

Neurotransmitters determine how you think and feel as they whiz around your brain and nervous system. Your mood, alertness, enthusiasm, ability to relax – your love of life – are all affected by the different kinds of neurotransmitters, or different levels of their activity. We all seek physical and emotional comfort. We want to feel good. The action of neurotransmitters plays a significant role in feelings of pleasure and well-being, hence a deficiency or excess of any neurotransmitter will give rise to uncomfortable feelings.

We choose actions for the rewards they give us

The interactions of neurotransmitters have an incredibly powerful effect on our emotions and thinking. Some of them act as stimulants. Some act as relaxants, stopping us from getting too hyper or stressed. As these stimulators and inhibitors act upon one another, a chemical cascade is formed, intended to result in a feeling of pleasure. This is how our brain rewards us. Most of the actions we take are chosen to produce this feeling of reward. We eat because it produces a reward of good feelings. We eat certain foods because they produce a better reward than others (chocolate produces more reward for most people than broccoli, for example). We have sex because it produces a powerful release of pleasurable chemicals. We work because the work itself is rewarding for us or because the end result produces a reward. We refrain from certain actions because they do not produce the feeling of reward we are seeking.

A word of praise for a job well done acts as a stimulus that activates a chemical reaction in the brain that feels good. A hug from a loved one sets off a brain chemical interaction that acts as a reward. The way we think, feel and behave results from chemical interactions in the brain and, in turn, produces additional chemical reactions in the brain. When the result of an action is positive, it reinforces that behaviour and motivates us to repeat it. So we tend to repeat actions that cause us to feel relaxed, happy, satisfied, complete and fulfilled.

The most important neurotransmitters

Although there are hundreds of neurotransmitters, the following are the main ones:

Dopamine, adrenalin and noradrenalin (adrenalin’s cousin) are the ‘feel-good’ neurotransmitters, making you feel energised and in control. When you have adrenalin, dopamine and noradrenalin in balance you feel stimulated and energised. (Noradrenalin is called norepinephrine in the US.) Adrenalin is also the ‘motivator’, stimulating you and helping you respond to stress.

Endorphins and enkephalins promote a feeling of bliss, giving you a sense of euphoria. They are also painkillers, relieving both physical and emotional pain. They make you feel good.

Serotonin is the ‘mellow’ neurotransmitter, improving your mood and sleep, and banishing the blues. With an adequate supply of serotonin, you feel more confident, emotionally stable and connected.

GABA (gamma-aminobutyric acid) is the ‘chilled’ neurotransmitter, reducing anxiety, relaxing you and calming you.

Taurine helps promote GABA and also promotes calmness, helping you to relax and to sleep.

These are the key players in the orchestra of your brain and nervous system. The simple secret of feeling great is to have the right balance of these neurotransmitters. The trick to doing this is to eat the right foods and supplement the right nutrients from which your brain makes and controls these neurotransmitters.

The balancing act: why we might take harmful substances

The problem is that if you have an insufficiency in one or more of these neurotransmitters, your brain will be out of kilter, like a car out of tune. For example, 82 per cent of people with depression have very low levels of serotonin and 73 per cent have very low levels of noradrenalin.14

Instinctively your brain will crave anything that corrects a deficiency. This can be provided by nutrients, but too often we take other substances instead.

As you will see, that is why we end up using other substances that mimic or enhance the feel-good factor of our own natural neurotransmitters.

Amino acids: the tools for unaddicting our brain

Neurotransmitters are manufactured in the neurons from amino acids, the building blocks of protein. Different amino acids produce different neurotransmitters, as seen below:

L-phenylalanine increases dopamine and noradrenalin

Tryptophan, and 5-hydroxytryptophan (5-HTP) increases serotonin and melatonin (melatonin helps you relax and sleep)

Tyrosine increases dopamine and noradrenalin

Glutamine increases GABA and glutathione, which in turn increase enkephalin levels

GABA is an amino acid and also a neurotransmitter

Taurine is an amino acid and also a neurotransmitter

Cysteine increases levels of glutathione

The two forms of amino acids: D- and L

Most of the amino acids have two forms, the chemical structure of one being the mirror image of the other. These are called the D- and L- forms. Foods generally contain the L- forms. All of the amino acids recommended in this book for the management of addiction are the L- form, with one important exception: phenylalanine, which is used in both forms.

The chart below lists the neurotransmitters, the feelings that they provide for us and the essential amino acids that they need to function properly.

NEUROTRANSMITTERS AT A GLANCE

Neurotransmitter What it does Amino acid it’s made from

Adrenalin, noradrenalin Arousal, energy, stimulation, mental focus L-phenylalanine, tyrosine

Dopamine Pleasure, comfort, satisfaction and a sense of fullness after eating L-phenylalanine, tyrosine

Endorphins, enkephalins Physical and emotional pain relief, euphoria, pleasure, good feelings, sense of well-being D-phenylalanine, DL-phenylalanine

Serotonin Emotional stability, self-confidence, pain tolerance, quality sleep tryptophan or 5-HTP

GABA Calmness, relaxation and seizure control GABA, glutamine

Taurine Calmness, promotion of sleep, and digestion seizure control taurine

Remember these amino acids, because these are the tools you are going to use to un-adict your brain, to give your brain what it really needs to stay in balance and to reward you with good feelings.

A good example of the relationship between amino acid intake and how we feel is demonstrated by an experiment on the effects of tryptophan. In the preceding list you can see how the neurotransmitter serotonin is made from the amino acid tryptophan, which gives us emotional stability, self-confidence, pain tolerance and quality sleep. A lack of tryptophan has marked effects, as was shown very clearly by an experiment carried out at Oxford University’s Department of Psychiatry. Fifteen women were given a diet devoid of tryptophan (found in turkey, dairy products, green leafy vegetables, bananas, pineapple, avocado, soy, lentils, sesame seeds and pumpkin). Within eight hours, most of them started to feel more depressed. When tryptophan was added to their diet, their mood improved.15

Essential fats: making sure the message is received

Your brain, if you discount water, is 60 per cent fat, so eating the correct fats is essential for a healthy brain. In our explanation about neurotransmitters so far we’ve been looking at ‘talking’ – the way neurotransmitters deliver messages. If we now look more closely at ‘listening’ – how the receiving neuron gets the message – it soon becomes clear how vital the correct fats are for your brain.

At the synapse, brain cell membranes are also composed in part of essential fats and cholesterol, surrounding and supporting receptor sites – we can think of receptor sites in this context as the ears receiving the messages. So, to get the correct message from one brain cell to another, you need a good supply of essential fats and cholesterol.

The synaptic membrane of neurons is composed of phospholipids and fats

Essential fats and phospholipids: helping you to crave less

Looking even closer at the brain cell membrane we find that it is made out of cholesterol and a type of nutrient called a phospholipid, with two fats attached: an unsaturated fat and either DHA (docasehexaenoic acid), a type of omega-3 fat, or arachidonic acid, a type of omega-6 fat.

By eating and supplementing the perfect amount and combination of essential fats, cholesterol and phospholipids you become much more receptive to your own neurotransmitters, which means you crave less. Eggs contain cholesterol and are very rich in phospholipids, as are brains and offal. You might not fancy eating brains or offal, but the smartest animals do. A fox, for example, will eat the heads and leave the rest unless very hungry. (Do you suppose they eat the heads because they are as smart as a fox or do they get smart as a fox by eating brains?)

We’ll show you how to achieve the perfect intake of both essential fats and phospholipids (without eating brains) in Part 2.

Methylation: the conductor of the orchestra

How can your body’s chemistry ebb and flow, creating harmony with your thoughts and emotions? The complexity and intelligence of your body’s design is incredible. Probably the single most important conductor of your brain’s orchestra is a process called methylation.

Your mood isn’t just dependent on how much tryptophan or phenylalanine you eat; it also depends in part on how efficient you are at turning amino acids into neurotransmitters. That’s mostly determined by methylation. Methylation reactions happen a billion times every couple of seconds and are totally dependent on nutrients. The process helps make, break down, and balance neurotransmitters, build nerve cells and protect your brain from damage (even slowing down the ageing process).

Methylation is the conductor of your orchestra so if you want to make sure you are in tune – feeling good, happy, alert and connected – you need to ensure you are a good methylator. Most people who need a substance to feel good are not good methylators.

Having the right connections

For us to feel well, our bodies need to be efficient at methylation, because that ensures the chemical connections are made quickly, and when that is working we will crave less. Here’s an example of how fast chemical connections can be made in our body. If you have a near miss while driving your car, within 0.2 of a second your body begins to pump adrenalin. This is how it works: noradrenalin, the chemical cousin of adrenalin, is floating around your bloodstream all the time; by adding on a tiny molecule called a ‘methyl group’ it turns into adrenalin. By the time you’ve read this sentence you’ve already done about a billion of these methylation reactions, but in a stressful situation this process is greatly speeded up so that you can act quickly. The ability of your body to do this literally determines how well ‘connected’ you feel.

How being a good methylator reduces cravings

To reduce your cravings for unhealthy substances you need to raise the equivalent of your methyl IQ. First, you need to find out what your methyl IQ is at the moment by measuring a substance called homocysteine in your blood (don’t worry, this is explained in detail in Chapter 9). If your homocysteine level is high, you’re not firing on all cylinders. See the case of Chris below for an example of what happens if you have a high homocysteine level.

Normally, homocysteine is converted into the amino acid S-adenosyl methionine, nicknamed SAM (sometimes called SAMe, pronounced ‘sammy’). SAM does all this methylation – it’s called a methyl donor and literally whizzes around the motorways of your mind donating methyl groups, building or changing one neurotransmitter into another. This conversion process, from the ‘bad’ homocysteine to the ‘good’ SAM, depends on B vitamins (B2, B6, B12 and especially folic acid), plus zinc and something called tri-methyl glycine (TMG). Now, when you eat your broccoli (which is high in folate), you can perhaps visualise your methyl donor whizzing to the scene of the crime, perhaps to raise your serotonin and dopamine levels and make you feel happier.

Case study CHRIS

Chris was feeling brain-dead. His mood and motivation was lousy. His memory was appalling – he kept losing his car in multi-storey car parks. His sex drive was non-existent. His homocysteine was 119. After a year taking all the right homocysteine-lowering nutrients his homocysteine has dropped to 9 and he’s a transformed man. ‘My memory and concentration are better than ever. My mood is great. My energy levels are amazing – in fact I now exercise each morning for an hour because I feel so good.’ Last time we spoke to Chris, who is now 60, he was telling us about his new young girlfriend – so everything’s working in that department. The key is getting your homocysteine down.

Poor methylation equals addiction and cravings

There’s no question that just about everything we associate with addiction and cravings is related to poor methylation, reflected by high homocysteine and low SAM levels. So, what you want in your brain and bloodstream is low homocysteine and high SAM levels. How do you raise your methyl IQ? There are three answers:

1. Stop doing the things that tax the system, raise homocysteine and mess up methylation – and that includes cigarettes, excessive caffeine and, especially, coffee, alcohol and other drugs. (A double espresso raises your homocysteine level by 11 per cent in four hours.)

2. Take B vitamins (B2, B6, folic acid, B12) and the minerals zinc and magnesium – these are the co-factor nutrients that methylation depends on.

3. Make sure you’ve got the building blocks of SAM in the first place – that means enough methionine from protein, tri-methyl glycine (TMG) from root vegetables, and folate from green leafy vegetables. (Exactly what to eat, what not to eat, and how to supplement is explained in Chapter 9.)

Helping your brain help you to feel good

Putting together everything you’ve learned so far, you’ll see that there are three ways to improve your neurotransmission, and hence reduce your cravings and recover your natural energy, mood, get-up-and-go, mental clarity and alertness.

1 Better talking

To ensure ‘better talking’ your body must make large enough quantities of the neurotransmitters you need. This means supplying the body and brain with the amino acids and co-factor vitamins and minerals (needed to help the amino acids work) that are the building blocks of the desired neurotransmitters (explained in more detail in Chapter 7).

2 Better listening

To ensure ‘bistening’ your brain’s cell membranes and receptors need to be in tiptop condition. This means consuming optimal amounts of the building materials for these receptor sites: essential fats, especially omega-3s, phospholipids (explained in more detail in Chapter 10) and the right amount of cholesterol.

3 Prevent down-regulation

Avoid addictive substances that make you less sensitive to your own feel-good brain chemicals. This process of becoming less sensitive is called down-regulation (see page 52).

Three ways to improve neurotransmission

Case study JANE

Jane lives alone and doesn’t eat a very well-balanced diet. She’s lacking the amino acid tryptophan and feeling lonely. As a consequence she is often depressed. She uses alcohol to relieve her depression. She decides to stop drinking alcohol, improves her diet, and supplements tryptophan (or its cousin, 5-hydroxytryptophan). As her serotonin levels improve, so does her mood.

She starts to eat more fish (high in omega-3 fats) and adds a spoonful of lecithin granules (high in phospholipids) to her breakfast. Her mood becomes more stable and she starts to experience a consistently higher level of mental energy. She feels more confident. Following our recommendations in Part 2, including eating a great diet high in essential fats, and taking specific supplements of amino acids, vitamins and minerals, plus regular exercise, which naturally boosts serotonin, Jane is off antidepressants and no longer feels she needs mood-boosting drugs.

As we have seen, addiction and cravings are the result of chemical changes in the brain, so what happens to cause us to become dependent? Why can’t we just stop taking the substance? In Chapter 3 we explain how we get hooked.

SUMMARY

The brain passes messages from one brain cell (neuron) to the next by way of chemicals called neurotransmitters.

Neurotransmitters work together to create feelings of pleasure to reward us for behaviours that keep us alive and comfortable.

Neurotransmitters are manufactured in neurons from amino acids, the building blocks of protein.

Neuron cell membranes at synapses contain receptors that receive messages sent from another neuron.

The brain cell membrane is very high in fat, so to receive the message we need a good supply of essential fats in our diets.

Methylation is required for the process of turning amino acids into neurotransmitters.

A substance called S-adenosyl methionine (SAM) – converted from a substance called homocysteine, which is made from the amino acid methionine – is a ‘methyl donor’, because it is a fully loaded amino acid that can help balance neurotransmitter levels as needed.

To increase methylation, stop taxing your system with harmful substances, then get enzymes working at peak efficiency by optimising your intake of B vitamins, zinc and magnesium

How you become dependent

2014-05-08T05:50:00.000-07:00

Now that you’ve got a basic understanding of how your brain works to change how you feel, let’s look closely at how you get hooked on addictive substances. No one intends to become addicted. No child says, ‘I’m going to be an alcoholic when I grow up.’ No adolescent who experiments with drugs thinks, ‘I want to become a junkie.’ No one, when taking the first puff, drink, sniff, pill or injection, plans on getting addicted to cigarettes, marijuana, caffeine, alcohol, cocaine, speed, prescription medication or heroin. Yet for a great number of people, that first drink, smoke or hit leads, deceptively and often slowly, to physical dependence.
Mood-altering substances change the balance of the neurotransmitters in your brain and nervous system. They sensitise the brain to drug-related stimuli, and alter brain ‘organisation’.

Why the brain gets hooked

It is impossible for anyone who has never been chronically addicted to comprehend the power of addiction. It seems logical and reasonable to stop doing something so harmful to yourself and others, especially those you care about most. But the addiction process does not involve the part of the brain that is reasonable and logical. It involves a part of the brain called the limbic system. This is the brain’s pleasure and reward centre; concerned with our survival, it is the part that tells us to eat, drink, fight or take flight. It monitors the body’s need for survival, and when it senses our survival is dependent on a certain behaviour it creates a compulsion so strong that it becomes extremely difficult to resist taking that action. Without it we might forget to breathe or eat or reproduce.
How addiction becomes like survival

As you become hooked on any substance, this part of the brain begins to react to the presence or absence of the substance as it does to the need to eat or breathe, as though it is a substance necessary for survival. The reward systems of the brain may become hypersensitive (‘sensitised’) to drug-associated stimuli so that anything associated with drug use sets off a craving for the drug, even after the drug experience is no longer pleasurable.
We should point out that in the later stages of addiction to some substances, such as alcohol, withdrawal can be so serious that it is possible to die as a result. In the case of nicotine, caffeine or sugar you will not die, but the reward system doesn’t distinguish between those circumstances when we might die and those when we feel that we might.
How the brain is tricked

To understand this process completely, it is important to know that the neuron’s receptors will also accept mood-altering chemicals that mimic natural brain chemicals: dopamine, serotonin and endorphins. In other words, mood-altering chemicals can sneak into the letterbox (as we described on page 34) intended for neurotransmitters like dopamine and serotonin and fool the brain into acting as though they are the real thing. For example, cocaine docks onto the receptor for dopamine; heroin mimics endorphins, fitting into the same docking port; and alcohol mimics GABA. That’s why these substances make you feel stimulated, motivated, euphoric or relaxed. They are taking over the role of the natural substances.
Any substance you crave, or any substance that makes you feel good, is either promoting your ability to make or restore the balance of your neurotransmitters, or it can mimic the neurotransmitter, docking onto its receptor site.

A short explanation of addiction

Probably none of us would become addicted if nature had not built in a mechanism whose goal is to prevent us from being too elated for too long. Remember the kick from your first cigarette, alcoholic drink or coffee? Have you ever wondered why you don’t experience that any more? Why do you need more and more caffeine, nicotine, alcohol or drugs to get the same effect, or at least to keep thinking that if you only had a little more you would get the same effect?
When we boost our feel-good neurotransmitters, as we do with a cup of coffee, a cigarette or a drink, the dopamine released causes a feeling of well-being. However, in response, the receptors gradually shut down, deflating our high. A key concept in the body and brain, as in all of nature, is balance. Much as a thermostat keeps our home at a desired temperature, our body has ways of maintaining a state of equilibrium. It doesn’t want us to be too high for too long! Is nature a killjoy? A likely explanation is evolution. Blissed out, happy monkeys get eaten. It’s the paranoid, edgy, pessimistic ones, who are always on the lookout, who survive!
Why you become dependent

In response to an increase in the amount of neurotransmitter available – for example dopamine from drinkng coffee – there is a ‘down-regulation’, a desensitising of the receptor sites. This means that some receptor sites shut down, making the neuron less responsive. Consequently, you need more of the substance – caffeine, nicotine, cocaine or whatever – to release neurotransmitters into the synapses and get the message across. It’s as if, in order to block out the yelling of the neurotransmitters, the receptors put on earplugs, leaving the neurotransmitters no alternative but to yell even louder.
The body’s self-regulation process, then, makes it impossible for us to gain any long-term benefit from the mood-altering substances. Herein lies the rub. The net result of addiction is that once the initial effect has worn off, the body’s normal ‘talking voice’ just isn’t loud enough to get the now-somewhat-deaf neighbouring cells excited. So you need more and more. No longer will that regular cup of coffee (around 100mg of caffeine) give you the kick-start you need. You need a large ‘special’ coffee (around 400mg), perhaps with a cigarette thrown in, or even a mochaccino (chocolate plus coffee – two different sources of caffeine), or some coke or a stimulant drug.
The desired effects get less and less

Of course, the more you have and the more often you have it, the more your brain cells ‘down-regulate’ by shutting down receptor sites. Continue along this slippery path for long enough and the effects of the substance become nothing like they used to be. The cup of coffee that gave you a rush of energy, now only relieves your ever-increasing fatigue. You need it just to feel normal. You’ve been trying to cheat the system and it’s fighting back.

Down-regulation and up-regulation

So why don’t you stop? For most of us wanting the substance becomes the driving force, not necessarily liking it. Your desire for the substance becomes almost irresistible when you’re in the setting or situation, or with friends that you associate with the substance, or even when you see something that you associate with it. This makes you crave the substance even though it doesn’t really work for you any more.16
What happens when you stop?

Unfortunately, by the time you realise this and stop using the substance, your body’s chemistry doesn’t give you an unconditional pardon. Two things have been occurring. The reward system has become sensitised to the regular intake of the addictive substance to the point that anything associated with drug use can trigger severe craving and the sense that life depends upon continued use. For example, if you have associated smoking with a cup of coffee, then a cup of coffee following a meal may trigger a craving for a cigarette so strongly you can feel you might die without it. In addition the brain has adapted to the intake and punishes you with withdrawal when you stop using the substance. In effect, the withdrawal period is the time it takes from the moment you quit using stimulants until your neurons ‘up-regulate’ to hear your neurotransmitters’ normal speaking voice once again. In the case of caffeine this is only a matter of days. For nicotine or heroin it can take weeks. In many cases it never recovere. less you follow our How to Quit programme, which provides an adequate supply of nutrients that nourish and repair the brain.
Does this happen to everyone?

Before we go on, we need to point out that this does not happen to everyone who drinks alcohol, smokes cannabis, tries cocaine or drinks coffee. Some people have a form of a gene that causes the reward receptors in the brain to become rapidly sensitised to the drug.17 Other people may have a form of a gene that causes them to be deficient in certain neurotransmitters or receptors.18 There may be other genes or combinations of genes or environmental factors that cause other people to be more susceptible to becoming addicted.19

Case study JAMES AND RICHARD

James and Richard are brothers. As teenagers they took drugs together. They used the same drugs in the same quantities. But as they reached college age James began to see that his drug use was interfering with what he wanted out of life. He quit using illegal drugs, though he continued to drink infrequently and always in moderation. But by the same age Richard realised that what he wanted out of life was drugs. James enrolled in college, established a career, had a family and became politically active and a respected member of his community. Richard enrolled in college, too, many times; but he never completed a term before some drug-related incident interfered. He got married a couple of times, but when each of his wives asked him to choose between them and drugs, he chose drugs. He is now in prison, serving an 18-month sentence for possession of cocaine.

What was different in these brothers? To answer this we need to look at what happens in the brain of some people that predisposes them to be more susceptible to becoming dependent on mood-altering substances.
Reward deficiency can lead you to addiction

Remember that in the last chapter we said that when your brain is working properly it rewards you? It creates a sense of well-being, pleasure and satisfaction with normal activities. But what happens when the brain is not working like this? When there is too much of one neurotransmitter or not enough of another, it sends out a powerful message to correct the imbalance. We become restless and anxious, feel empty, unsatisfied and have vague or specific cravings.
When your brain does not provide the normal reward, you will often feel as though you are constantly in need of something to fill the emptiness, reduce the anxiety, soften the environment, elevate the mood, quiet the restlessness or satisfy the cravings. People in this state are reward-deficient and look for something to relieve the imbalance and help them feel good. This is the brain telling us to take action to correct the imbalance. When you do not find healthy ways to do this, you will find unhealthy ones. You might think that the reward-deficient person would crave what is good for them (like broccoli) rather than what is not good for them (caffeine). Much of the time they don’t know what it is they are craving. They are just seeking something to satisfy the lack, to fill the feeling of dissatisfaction, like when we eat something when really we are thirsty. Broccoli, for example, doesn’t provide the almost-instant lift that coffee does, even though in the long run broccoli might help correct the imbalance – but coffee works in just 15 minutes. For some of us, however, that isn’t fast enough and we find that cocaine does it better and faster – in 15 seconds. Crack, on the other hand, does it instantly. Now you’re in heaven, heading for the hell of reward deficiency.
What causes reward deficiency?

There are many causes of reward deficiency, and it’s worth going through a few of the major ones.
Genetics Some people are born with a genetic make-up that interferes with normal brain chemical balances so that mood-altering substances become more appealing. Studies have shown that numerous genes are associated with conditions that manifest as symptoms of reward deficiency.20 There’s growing evidence that if you inherit fewer receptors for dopamine you will be more likely to choose substances such as alcohol, and to become addicted.21 It’s a hot and complicated area of research.22 Among the inherited conditions linked to reward deficiency is ADHD. In fact, there’s a strong link between ADHD symptoms in a child and addiction as an adult23 and people with ADHD are more likely to have the genetic tendency to reward deficiency.24 Many ADHD kids are reward-deficient and so they seek stimulating behaviour such as being hyperactive and taking risks to stimulate their brains into giving them what they don’t have naturally. Alternatively, they may become addicted to sugar and caffeinated drinks, and in adolescence they may begin using nicotine and alcohol and, frequently, illegal substances.
People born with the genetic predisposition to reward deficiency are more likely to become addicted.

Case study TWILA

Twila’s father was an alcoholic. Although she didn’t realise it while she was growing up, looking back on it, Twila realises that her father also had symptoms of adult attention deficit disorder. She was diagnosed with ADHD as an adult recovering alcoholic. In remembering her childhood, she recalls that she was always restless, had difficulty concentrating, felt high levels of anxiety, was easily stressed and was distracted by noise and competing sounds. She remembers that she never felt comfortable, at ease or satisfied. She believed there was something seriously wrong with her, but she had no idea what it was. She just knew from an early age that she was different. It wasn’t until she discovered alcohol in her early teens and began using it to change her brain chemistry that she began to fit in and feel comfortable and satisfied. Twila was probably born with reward deficiency that she inherited from her father. And her reward deficiency put her at risk of addiction.
One way in which your genes could tip you towards reward deficiency is fewer receptors for the feel-good neurotransmitter dopamine because of an abnormal form of the D2 receptor gene. In effect, this form of the gene renders the dopamine system inefficient.25 The number of dopamine D2 receptors are consistently lower among substance abusers.26 Inheriting this tendency is associated with more severe problems with alcohol.27
Non-genetic causes of addiction

Although the risk of addiction is very high among those genetically predisposed, reward deficiency can also result from non-genetic causes.
Prenatal conditions such as malnutrition or use of alcohol or drugs by the mother during pregnancy can result in conditions related to reward deficiency. Plenty of research has linked drinking during pregnancy with the risk of numerous problems in children, including behaviour, attention and impulse problems, alcohol disorders and even criminal behaviour.28
Malnutrition As we have already explained, neurotransmitters are produced from amino acids, vitamins and minerals, many of which are derived from food. So if you eat poorly over an extended period of time this can weaken the production and interaction of brain chemicals. Malnutrition can result from very low-calorie dieting, anorexia or bulimia, an unidentified food allergy (perhaps to gluten), or a diet simply lacking in adequate nutrition (due to any number of causes). When these ‘building block’ nutrients are lacking, the neurotransmitter system breaks down.
Severe or ongoing stress can do long-term damage to the reward system of the brain. This may be in the form of a single traumatic event (such as if you were in an earthquake or witnessed a murder), intermittent or chronic stressful events (such as child abuse), a series of highly stressful situations (a death followed by a serious injury followed by the loss of your job), or an ongoing condition of unrelenting stress (if you live with an alcoholic or drug-addicted person). It’s important not to underestimate the relationship between extreme stress and altered brain chemistry. When you are under normal stress, your brain’s neurotransmitter balance returns to normal as the stress passes. But when stress is severe or prolonged, these chemical levels may never return to normal without the correct nutrients to repair the damage. And when you are in a state of chronic stress you are more likely to turn to the use of mood-altering substances to lower it.
Lack of sleep If you go without sufficient sleep on a continuous basis this can also lead to reward deficiency. As you’ll see in Chapter 13, sleep is a vital component of health. In fact, it’s how the limbic system (the part of the brain involved with addiction) discharges negative, unexpressed emotions from the day before. Without enough sleep the stress and tension builds up and upsets the brain’s normal night-and-day cycle of feel-good neurotransmitters.
Physical trauma Damage to the head can also lead to an imbalance in the brain’s chemistry. Damage to the brain caused by the brain slamming against the skull results in many of the symptoms we have been describing and is frequently diagnosed as some other condition such as ADHD.
Heavy or long-term use of mood-altering substances can alter brain chemistry. So people who may not have the gene or be malnourished or traumatised may develop reward deficiency just by their excessive use of mood-altering substances. This is especially true if the chosen substance is a super-addictive substance (discussed below).
Not all drugs are equal

Your risk factors for reward deficiency are not all there is to consider. Although your genes are a strong risk factor, the risk of addiction also depends upon which drug you use and how you use it.
How susceptible you are + the addictiveness of the substance + the frequency and quantity of use = your risk of addiction

But then, of course, there are social factors too: the company you keep, the availability of the drug and other triggers in your life. Addiction is a complex business.
The super-addictive substances

There are some substances that are addictive to almost anyone who uses them. Nicotine is a good example. The majority of people who smoke for any length of time become addicted and find it very difficult to give it up. Nicotine has been reported by many researchers to be more addictive than crack cocaine. (This is unlike alcohol, which is only addictive to a minority of people who drink.) However, there are a few people who smoke without becoming addicted. These people may be able to quit cold turkey and can’t understand why other people cannot do the same. There are other people, usually those with a certain genetic make-up, for whom smoking is extremely addictive, who start smoking at a younger age and find it so difficult to quit that repeated efforts usually prove futile. Other substances that are super-addictive include the benzodiazepines (tranquillisers), which are exceptionally difficult to get off. If you are one of these people it does not mean that you are weak willed. It means that you need extra help to reset your brain’s chemistry and unaddict your brain. That’s where the nutritional approach contained in the How to Quit programme in this book will be able to help you.
Why we seek feel-good substances

Whether the cause of reward deficiency is genetic or environmental or a combination of both, it puts you at a higher risk of beginning to use a substance to relieve the discomfort of the deficiency and of becoming dependent on it. To understand this better let’s look at what happens when people with reward deficiency discover a substance that provides what they are missing.
When the normal process of neurotransmission is impaired, the discomfort that results can lead you to the use of mood-altering substances to self-medicate the discomfort. Remember that mood-altering substances fit into the same receptors as neurotransmitters or increase the amount of neurotransaddicted the synapse. So, if there is a deficiency, the appropriate substance becomes a substitute for the natural chemical and temporarily corrects the deficiency. Suddenly your anxiety, restlessness, emptiness, hypersensitivity and craving have gone. You may feel good for the first time in your life. But the substance does more than allow you to feel normal. The brain is flooded with the substance, which produces feelings of intense pleasure and euphoria.29
Are people who are reward-deficient more likely than the average person to continue using a mood-altering substance once they have found one that ‘works’ for them? Of course. It is highly unlikely that, having discovered a way to feel better instantly, you will not do it over and over again. And the reward is immediate. It works, it works now, and it works every time (at least in the beginning). It relieves your discomfort and gives you pleasure. You are no longer reward-deficient. You feel good – and perhaps you never knew that you could feel this good.
How mind-altering substances affect reward-deficient people

If you have reward deficiency you are likely to become addicted because the continued and regular use of the mind-altering substance works for what ails you. Also, if you have the genetic tendency to reward deficiency you are more susceptible to becoming addicted because it seems the very same genes that predispose reward deficiency also cause something different to happen in your brain when you use mood-altering substances. The experience for you is not just pleasant, but exhilarating. You get a higher high.
This is common, for example, among alcoholics. People with a genetic predisposition to become alcoholic do not metabolise alcohol in the same way as other people. Many people prone to alcoholism produce more of a liver enzyme called alcohol dehydrogenase II (or II ADH).30 This means they metabolise acetaldehyde (the by-product of the breakdown of alcohol by the liver) more slowly, allowing more of it to build up in the bloodstream.
The early warning signs

It is very difficult to detect addiction in the early stages because, for the people most susceptible, it is more beneficial to their daily lives than harmful. It provides what their brains lack normally. Just as Ritalin (a mood-altering substance) can allow some children with ADHD to function better, other substances are beneficial for other reward-deficiency conditions and allow improved functioning and performance. With alcohol, in spite of a common belief that as the quantity of alcohol consumed increases the ability to function decreases, some people may actually be able to perform some tasks better when a little intoxicated than they can when totally sober.
This early warning sign that addiction may be occurring (i.e. the ability to function well) makes it difficult for people affected to recognise they have a problem. The ability to ‘hold your drink’ (or drug) actually conceals the problem and creates the belief among early-stage addicts that they are immune to the painful consequences that they see others experience. It is difficult for a person who gets so much pleasure from a cigarette, or someone who gets such comfort from a piece of cake or someone who gets a much-needed lift from a cup of coffee, to believe the beloved substance can be harmful. Addiction is a condition that appears in the early stage to be a benefit, allowing you to experience the good feelings without paying any of the penalties.
Addiction: a gradual process

This is the process you will probably go through:
1. Tolerance You can consume larger quantities than other people without becoming impaired. You gradually increase the amount you use to get the same effects, still without becoming impaired.
2. Painful consequences You begin to experience the consequences of using the substance but often do not connect the consequences with use. You then use the substance to relieve the pain of using.
3. Dependence Now you need the substance to function, so regular use is necessary. When you don’t use it you experience withdrawal symptoms. So now you need to use it to relieve the pain of not using.
4. Tolerance decreases It is impossible to consume the same amount as before without suffering. The magic is gone and the painful consequences are worse. Now there is pain whether you have it or not. At this point many people choose to do something about the problem.
5. Abstinence symptoms Even after the acute withdrawal symptoms are gone, there are lingering abstinence symptoms that don’t improve with time.

Developing tolerance

Your brain changes and adapts to you taking the substance regularly. If you are becoming addicted to alcohol you can gradually tolerate larger and larger quantities without becoming intoxicated and without experiencing harmful consequences. If you are becoming addicted to caffeine you can gradually increase the amount of coffee you consume without becoming overstimulated and jittery. This is tolerance. But, over time, continued heavy use, especially if you have a genetic predisposition, will lead to addiction.
The more you consume, the more your brain adapts to the presence of these large quantities until you must use larger and larger quantities to get the same effect, causing more and more changes in the brain.

Case study TWILA

Twila knew from the first drink that she would continue to use alcohol to feel good. She knew immediately that it took away all the things about her that always made her feel different. At first she could drink with no problems. She could drink larger quantities than her friends could without getting drunk. She was able to function better when she had a few drinks than she could sober. She felt freer to express herself. She started writing poetry and thought she had found or released the creative part of her. She found that as she drank more, she was able to drink even more, then began to find that the amounts she had used before no longer did for her what they used to, and she increased the frequency and quantity of her drinking. She was unaware that neurochemical changes were taking place that were setting her up for problems. She thought she was in no danger of becoming addicted because she could ‘hold her drink’ better than anyone she knew. She was not aware that this was an early warning sign of alcoholism. Alcohol was her best friend and, she thought, her friend for life.

Although Twila’s story is about an addiction to alcohol, this same progression applies to other addictions.
Painful consequences

When you are into heavy and continuous use of addictive substances, the good feelings produced at first are eventually negated by the painful consequences. This can come in many forms: weight gain from excessive sugar, indigestion from too much caffeine, the frustrated response of trying to function while waiting for a cigarette. Problems may arise from drinking and driving or other encounters with the law. Or there may be problems from a ‘nagging’ family who want you to cut down. Or there may be any number of physical complications. Whatever the problems are, you know a way to make the pain of them go away. So you are now using addictive substances to relieve the painful consequences of using addictive substances. The more pain, the more use. The more use, the more pain. The substance blocks the awareness of what is really causing the pain. It’s a vicious cycle.
What is happening in the brain at this point, is that the mood-altering substance is interfering with the release of neurotransmitters and/or blocking the receptors. So, with heavier use, there are fewer neurotransmitters being produced and released than before. And it takes more and more of the substance to fill the receptors and get high – and now the receptors may no longer be working properly.

Case study TWILA

So what happened to Twila? To her surprise, she began to have problems while she was still a teenager because of her drinking. At first she did not realise that these problems had anything to do with drinking. She began skipping school and thought she was just having a good time. When she was caught and punished at home and suspended from school, she told herself everyone was just over-reacting to her free spirit. She felt misunderstood, and she comforted herself by drinking more.

Becoming dependent

When dependence is increasing most people are unaware that physiological and biochemical changes are occurring as long as they are able to drink, smoke or get their ‘fix’ of sugar or caffeine. They think they are functioning normally. And they may believe they are drinking, smoking or taking drugs responsibly. When enough problems occur, they may attempt to cut back. But by the time they are aware that use of the substace is the problem, they cannot choose to use it in moderation. As the brain adapts to higher levels of the substance, the body accepts this as normal and demands that this ‘normality’ be maintained.
So while tolerance is increasing, so is dependence. ‘Want’ becomes ‘need’. There is a growing need to use the substance. Craving for the substance leads to continued substance use in spite of the painful consequences. The person cannot function without it.
As neurons in the brain adapt to larger and larger quantities, the brain becomes reliant upon the mood-altering substance and shuts down its own production of neurotransmitters.

The hijacked brain

Your brain does not need to keep producing its own feel-good neurotransmitters because the receptors are being filled by copycat substances. When the brain does not get its supply from an outside source, it does not snap into production and start supplying the needed chemicals. Instead, it screams out for more of the ingested substance. This is when the survival part of the brain takes over. It believes it must have the substance to survive. It overpowers the rational part of the brain, and getting the substance becomes as strong a need as breathing. This has been called the ‘hijacked brain’ – the drug has stolen your ability to make rational choices.

Case study TWILA

So how did Twila’s drinking affect her? When she got married, her husband objected to her heavy drinking, so she decided she would cut back. But her attempts were short-lived. She would cut back for a few days and then find that she was back to her regular amount. As this became more and more of a problem in her marriage, she tried many ways to drink in moderation. She would set rules and break them. She would promise herself she would drink only during certain times of the day. Or she would drink only at weekends. Or she would drink only beer. Or she would drink only with other people. But all her promises to herself and to her husband were broken. Fearing her husband was going to leave her, she promised to quit entirely. And she did. For two days. She was sick and miserable for those two days. She never stopped thinking about drinking. She was obsessed with the idea of having ‘just one’. The compulsion to take that one drink was overpowering. Finally, convinced she could have one and stop, she gave in and soon her drinking was out of control again. Her husband did leave her and then she felt she had a real reason to drink, and alcohol took over her life.

The pain of abstinence

Your great friend now becomes your enemy. The substance now creates pain instead of producing pleasure, and now instead of being able to tolerate more, you can tolerate less and less. You have pain when using the substance and pain when not using it. The drug has depleted the brain’s supply of natural feel-good chemicals, the receptors are not working as they should and the drug is no longer a satisfactory substitute. You might continue to use food, alcohol, nicotine or other drugs, prescribed Shrwise, not for any substantial pleasure, but only because the survival part of the brain has taken over and believes it must have the substance. You find your attempts to stop are usually short-lived and futile and you suffer from severe anxiety when an unexpected situation interferes with the substance use or the source of supply.
When you continue to use despite serious consequences, other people believe you to be behaving irresponsibly, unaware that you are not consciously choosing the behaviour. It is being dictated by the survival part of the brain. You may go immediately from the pain of needing the drug to the pain of using the drug. The magic is gone. The pleasure is gone. There is nothing but pain.

Case study TWILA

Twila doesn’t remember when the pleasure stopped and drinking brought her only pain. At first she thought she was so miserable because her husband had left her. Gradually she became aware that drinking was giving her no comfort. She was getting drunk more and more often. She could drink less and less before getting sick. Where had the magic gone? She was convinced she could find it again if she could just find the secret door. She tried to work at several jobs but was too sick most of the time to go to work. She was lonely and started going out with friends with whom she previously drank, those people who used to talk about her ability to hold her liquor. But now she was passing out and they were driving her home. They didn’t like being with her any more. Every day she would promise herself that tomorrow she would stop. But tomorrow she only remade the promise.

Quitting becomes impossible

Sometimes seriously addicted people may have a moment of sanity when they realise that if they keep doing what they are doing they are going to damage themselves seriously or even die. They may ask for help. People with a nicotine addiction may go to some kind of stop-smoking programme. People who are diabetic or overweight because of an addiction to sugar might join a weight-loss programme. People with an addiction to alcohol, illegal drugs or prescription drugs may enter a treatment centre. If it is a treatment centre without medical detoxification, the pain of abstinence can be so severe that they leave before they have made it all the way through the detoxification process. If they get medical detoxification, many stick it out even though they are uncomfortable. But what happens now to the poor brain, totally depleted of natural brain chemicals and unable to produce an adequate supply? Usually nothing. It stays that way – perhaps for months, but often for years. It is reward-deficient, and more extremely so than before use of the substance began.
The discomfort, prior to substance use, is now even more intense. And the brain continues to crave the substance upon which it has come to depend. After struggling through months of pain and craving, many addicts give up in despair, and, believing there is no way out, go back to what they know will at least relieve the craving, if not the pain.

Case study IRENE

For 35 yearsht-losd weight controlled Irene’s life. She was overweight as a child and still remembers the pain of hearing people say, ‘She has such a pretty face,’ knowing that they were thinking, ‘It’s a shame she’s so fat.’ Throughout childhood, adolescence and adulthood, her life revolved around feeling the pain of being overweight and eating sweets to assuage that pain. She always knew she could ease it with her tried-and-true friend: sugar.
The first time she went on a diet her doctor told her that she could eat anything as long as it contained no white flour or white sugar. She immediately went home and baked a lemon meringue pie using brown sugar and wholewheat flour. Needless to say, it wasn’t as good as the ‘real’ thing, but she soon got used to the taste – and rapidly gained five pounds.
Later that year she decided to take the bull by the horns and just stopped eating altogether. The bathroom scales kept her on course for four days; it was saying great things. When her mother pleaded with her to be more sensible, she got out the cottage cheese, took a few bites, then reached for the biscuits.
Diets came and went, each beginning with strong determination and ending in despair. She tried commercial programmes, liquid protein, diets of the stars, diets of her friends, hypnosis and fasting. For a time she felt invincible. The world was her apple and that apple would always be eaten raw, never again in a pie. Despite her unceasing hunger for sweets, each time she dieted she lost weight. And sometimes she kept it off for a period of time through vigilant self-deprivation and icy determination. Then the ice would melt and the sugar craving would win. She watched her weight come back as if it had a life of its own.
Each time the craving was stronger than before, and she was more irritable and more easily stressed. Each time the unfairness of her plight, the burden of never-ending hunger, and never-ending vigilance overwhelmed her. Sweets called her name and she would eventually answer, ‘I’m back.’ She would reach out to her old friend, always there to soothe and comfort her.

Now, many people will tell you that Irene was just not motivated. But why would she do the same thing over and over again unless she really wanted to free herself from her addiction to sugar? She had controlled it over 20 times for a period long enough to lose weight. Why would you do again what you had failed at 20 times previously unless you wanted it very badly? Some people will tell you that Irene just did not have any self-discipline. How many of us have the self-discipline to endure ongoing, unrelenting pain – with no relief in sight – without looking for some source of pain relief?
How our How to Quit programme can help

Let us be clear here that many addicted people do make it and find ways to remain free of their addiction. Many find a better life through practising the principles of Alcoholics Anonymous (AA), Nicotine Anonymous, Overeaters Anonymous, or Narcotics or Cocaine Anonymous. Thousands of ex-smokers or drinkers or drug addicts are living proof that recovery from addiction is possible.
Through their experience of addiction and recovery they find meaning and purpose, and are able o live a happy life. Sadly, this is a minority. Some people are able to stop with the help of a counsellor or counselling programme. As important as counselling is, the majority do not achieve abstinence on a long-term basis, and those who do, often experience ongoing abstinence symptoms. Most treatment is helpful in that it helps addicts cope with the craving and pain of abstinence, but it does not take it away.
This is the missing link

With our How to Quit programme this can change for you and you can avoid relapse. Even those who have already been able to quit their addiction and stay off with the help of a 12-step support group or treatment programme can reduce the severity of their abstinence symptoms and improve the quality of their life. With our programme you can quit and begin to feel your abstinence symptoms improve in a matter of days. Some addictions are more serious and more difficult to overcome than others, but all addictions – whether to illegal drugs, prescription drugs, alcohol, nicotine, caffeine or sugar – have in common a need for restoring the brain to optimal functioning. Wherever you are along the road to addiction, you will find our How to Quit programme provides the missing link: when you fix the brain, you will find quitting and staying free of the need for substances so much easier.
SUMMARY

We use drugs to compensate for a lack of, or imbalance in, or dysfunction of, neurotransmitters.

When the reward system of the brain is working properly it creates a sense of well-being and satisfaction. Craving, dependence and addiction occur when the reward system goes wrong.

Many people born with the genetic predisposition to reward deficiency are also genetically predisposed to becoming addicted.

The more you have of a mood-altering substance the more insensitive your brain becomes to your own neurotransmitters. This is called down-regulation – it makes you more tolerant to larger amounts.

The more you consume the more your brain adapts to the presence of large quantities until you must use larger and larger quantities to get the same effect, causing more and more changes in the brain.

As neurons in the brain adapt to larger and larger quantities, the brain becomes reliant upon the mood-altering substances and shuts down its own production of neurotransmitters.

You now crave the substance and, if you don’t have it, you get withdrawal or abstinence symptoms.

Any substance you crave, or any substance that make you feel good, is either promoting your ability to make or restore the balance of your neurotransmitters, or is mimicking the neurotransmitter, docking onto its receptor site. Now you’re hooked

EFFECTS OF SLEEP ON VENTILATION

2014-05-08T05:19:00.000-07:00

State-related changes in CNS activity associated with the transition from wakefulness to sleep exert complex effects on ventilatory control that profoundly affect the level and pattern of breathing. In general, withdrawal of cortical and higher CNS influences that provide excitatory inputs to the medullary respiratory neurons during wakefulness cause the chemical regulation of ventilation to assume greater importance.
The transition from wakefulness to slow-wave sleep (i.e., stages 1, 2, 3, and 4 non-REM) is associated with increases in PaCO2 and decreases in PO2, an increase in the threshold of the ventilatory response to CO2, and elimination of the “dog leg” in the ventilatory response to CO2 attributable to the wakefulness drive. In normal subjects, elimination of wakefulness drives and decreases in chemosensitivity typically increase PaCO2 and decrease PO2 by 4 to 8 mmHg. Small reductions in PCO2 in the order of 4 to 6 mmHg regularly induce apnea in normal subjects, in contrast to what occurs during wakefulness, when breathing persists despite marked hypocapnia. Steady-state changes in PCO2 during slow-wave sleep appear to be inversely related to the magnitude of the ventilatory response to CO2 during wakefulness.
Breathing during stages 1 and 2 of slow-wave (i.e., light) sleep is frequently periodic and often characterized by apnea (i.e., cessation of air flow for >10 seconds) with or without occlusion of the airway (see below). Periodic breathing resembles the Cheyne-Stokes respiration occurring during wakefulness. On the other hand, stages 3 and 4 of non-REM sleep are generally characterized by a slow, deep, regular pattern of breathing. Interestingly, this phase of sleep is associated with a greater depression of ventilatory responses to CO2 and O2 than are stages 1 and 2.
Breathing during REM sleep is rapid and irregular, with marked variation in the duration of inspiration and expiration, tidal volume, and average inspiratory air flow rate. Periods of hyperpnea appear to coincide with REM sleep. Electrical activity (EMG) of the rib cage and upper airway respiratory muscles is profoundly depressed in REM sleep, in keeping with the marked muscular atonia observed in the limb muscles. Diaphragmatic EMG activity is relatively spared, but abrupt, irregular periods of inhibition during inspiration may occur. A disproportionate reduction in intercostal relative to diaphragmatic activity in REM sleep leads to paradoxical inward movement of the rib cage on inspiration. Profound inhibition of upper airway muscle electrical activity considerably increases upper airway resistance. Ventilatory responses to CO2 and O2 are at their lowest during this stage of sleep. In subjects with underlying lung disease, the greatest disturbances in PaO2 and PaCO2 occur during this stage of sleep, presumably because of the rapid, shallow pattern of breathing, increased ratio of volume of dead space to tidal volume, and uncoordinated pattern of rib cage and abdominal movement.
Periodic Breathing During Sleep
Recent studies have suggested several possible mechanisms for the periodic breathing and airway occlusion that occur during the transition from wakefulness to light sleep, each of which causes instability in the ventilatory control system. First, removal of the wakefulness drive depresses ventilation, with concomitant large and rapid increases in PCO2 and reductions in PO2 that stimulate peripheral and central chemoreceptors. Second, alterations in blood gas tensions and mild reductions in metabolic activity that decrease CO2 production and O2 consumption increase plant gain—that is, the change in blood gas tensions induced by a given change in ventilation. Increased plant gains in stage 1 and stage 2 sleep may offset the mild reductions in ventilatory responses to CO2 and O2 that occur during these stages and increase controller gain. Third, progressive increases in respiratory effort during occlusive apnea lead to arousal, the primary mechanism whereby occlusive apnea is terminated. Collapse of the upper airway and arousal destabilize breathing by producing large and rapid changes in PCO2 and PO2. Fourth, arousal may be followed by a rapid return to sleep, removal of the wakefulness drive, and rapid deterioration in blood gases. Cycles of airway occlusion and arousal superimposed on sleep-related changes in controller gain may be mutually reinforcing and lead to sustained, progressively amplifying oscillations in breathing and blood gas tensions. Breathing in stages 3 and 4 of sleep is likely to be more stable than in stages 1 and 2, because overall controller gain may be diminished and because changes in ventilation caused by external stimuli are less likely than in stages 1 and 2. Depression of CO2 and O2 chemosensitivity in stages 3 and 4 may more than offset increases in plant gain.
Changes in respiration with periods of apnea, profound arterial desaturation, and disturbed sleep appear to be especially common in patients with congestive heart failure. Periodic breathing in these subjects may be explained by a prolongation in circulation time with information delays and increases in plant gain as a result of decreases in pulmonary stores of O2 related to pulmonary edema.
Airway Occlusion During Sleep
The pathogenesis of airway occlusion during sleep has now been elucidated. Patency of the upper airway during sleep depends on a balance between the subatmospheric “sucking” pressures in the posterior nasopharyngeal space generated by the inspiratory muscles of the chest wall and the opposing dilating forces generated by the upper inspiratory airway muscles, which tend to enlarge and “stiffen” the upper airway. In essence, collapse of the upper airway during inspiration occurs when there is an imbalance of forces in favor of the subpharyngeal pressures. Collapse of the upper airway therefore depends on three factors: (1) activity of the dilator muscles, (2) intraluminal airway pressure, and (3) mechanical properties of the passive upper airway.
The activity of the respiratory skeletal muscles of the upper airways, which originate on the mandible, tongue, larynx, and hyoid bone and dilate the upper airway (i.e., genioglossus, geniohyoid, sternohyoid, posterior arytenoids, cricothyroid), demonstrate a respiratory modulation—that is, the EMG and tension of these muscles increase during inspiration, thereby augmenting the caliber of the upper airway and its tendency to remain patent. Hypercapnic and hypoxic chemical stimuli to breathing increase upper airway muscle electrical activity (e.g., genioglossus, posterior arytenoids) in a manner qualitatively similar to that seen in the pump muscles of the chest wall. All stages of sleep are associated with depression of EMG activity of upper airway muscles at any given level of PO2 or PCO2 out of proportion to changes in chest-wall muscle EMG. REM sleep is associated with the greatest inhibition of upper airway muscle electrical activity, in keeping with the generalized muscular atonia that occurs during this stage of sleep. Airway collapse during sleep is favored, therefore, by depression of the electrical activity of dilating upper airway muscles. Re-establishment of airway patency in the setting of obstructive apnea requires arousal and increases in upper airway EMG activity. Of interest, administration of alcohol in amounts that have no effect on ventilation or pattern of breathing depress genioglossus EMG activity during eucapnia or hypercapnia. This finding may explain the greater tendency for obstructive sleep apnea to develop after alcohol ingestion or sedative use.
In addition, end-expiratory lung volume (FRC) oscillates during periodic breathing and demonstrates progressive reduction during the several breaths preceding occlusion. Reductions in lung volume per se reduce the cross-sectional area of the posterior nasopharynx and increase the mechanical advantage of the inspiratory muscles of the chest wall (i.e., the inspiratory pressure generated for a given EMG activity is increased).
Classic control system theory indicates that increased controller gain predisposes to control system instability and oscillation. However, it seems likely that the precise mechanisms by which periodic breathing with apnea develop during sleep vary from individual to individual and may depend on the magnitude of the wakefulness drive, the propensity to awaken and undergo rapid, state-related changes in ventilation, and the proclivity of the upper airway to collapse.

Dorsal Respiratory Group

2014-02-23T16:26:00.000-08:00

The DRG contains almost entirely inspiratory neurons. One kind of inspiratory neuron, the Ia neuron, like the phrenic motor neurons, demonstrates an augmenting pattern of firing that peaks at end-inspiration. Axons from these cells decussate in the medulla at or immediately rostral to the obex and connect with phrenic and inspiratory intercostal motor neurons in the spinal cord. Collaterals are sent to the ipsilateral inspiratory neurons in the VRG, but a few also are distributed to the expiratory neurons in the VRG.
The firing of Ib neurons, as of Ia neurons, occurs primarily in inspiration but, in contrast to the discharge of Ia neurons, is augmented by inputs from pulmonary stretch receptors. In animals, the discharge peak of Ib is not as sharp and the decline in activity during expiration is slower than for Ia. In the absence of excitatory input from vagal stretch receptors, however, the discharge patterns of Ia and Ib neurons are similar.
Like Ia neurons, some of the Ib neurons project to the spinal cord. Those Ib neurons that do not project to the cord appear to undergo extensive axonal arborization in the NTS. Ib neurons seem to be responsible for the shortening of inspiratory time induced by lung inflation. Their responsiveness to stretch-receptor input is less during expiration than during inspiration.
The DRG also contains late-onset inspiratory neurons that reach their peak firing rate in the transition from inspiration to expiration. Their activity, like that of Ib neurons, is facilitated by stretch-receptor activity. These neurons may participate in the short phase of graded inhibition of inspiratory activity seen with volume changes occurring toward the terminal portion of inspiration.
Recently, a small number of early-expiratory neurons have been observed in the DRG (and possibly also in the VRG) intermingled with inspiratory cells. They begin their firing shortly before the end of inspiration and reach peak discharge rates quickly, and then their activity slowly diminishes during expiration, disappearing before inspiration begins. Increases in lung volume slow the rate of decline in activity of these cells, whereas prevention of lung inflation does the opposite. The activity of these neurons is related to postinspiration inspiratory activity (PIIA), which occurs in the diaphragm and intercostal and laryngeal muscles and retards expiratory flow and the rate of lung deflation.

Central Respiratory Neuron

2014-02-21T03:07:00.000-08:00

The precise organization of the central respiratory neurons is still a matter of contention. Although there may be respiratory pacemaker cells in which spontaneous changes in transmembrane potential occur, in the intact system, the respiratory rhythm depends on interconnections between different respiratory neurons.
Because breathing is preserved in anesthetized animals even after removal of the brain rostral to the pons, it is believed that the neurons on which respiratory rhythm critically depends are located in the bulbopontine region. Many investigators believe that the essential features of the respiratory rhythm remain even after separation of the pons from the medulla, and that the central pattern generator must be anatomically located within the confines of the medulla. There is evidence, however, that pontine neurons, particularly the complex composed of the nucleus parabrachialis medialis (NPBM) and the Kölliker-Fuse nucleus (KFN), as well as nuclei in the tegmentum (magnocellular and gigantocellular nuclei), significantly modify breathing.
In addition to these pontine and medullary respiratory neuronal aggregates, neurons with activity that is modulated by respiration can be found all through the brain stem intermixed with nonrespiratory neurons. It also has been shown that when breathing is stimulated, respiratory modulation of the activity of these neurons decreases according to level of anesthesia and sleep state.
A number of neurons whose firing patterns demonstrate a respiratory modulation but whose phase relationships with phrenic motor activity and with one another differ have been identified in the brain stem. Some of these neurons project to the spinal cord (bulbospinal) and are therefore true premotor cells. The remainder have axons that project to other parts of the brain (propriobulbar). Only the function of the bulbospinal neurons has been determined with any degree of certainty. It is generally believed, however, that the propriobulbar cells actively inhibit or excite other neurons involved in the respiratory cycle. The precise function of these propriobulbar neurons remains under investigation, although it is generally agreed that they are organized into networks whose complicated interactions determine the level of excitation of the bulbospinal neurons and produce respiratory phase switching.

CLINICAL IMPLICATIONS

2014-02-19T20:55:00.002-08:00

The most important cause of respiratory failure is derangement of lung mechanics. However, respiratory failure does not develop in all patients, even those with severe impairment of pulmonary function. It has long been suspected that those patients who have the poorest chemosensitivity are the ones in whom CO2 retention is most likely to develop when the performance of the chest bellows is reduced. The evidence for this is indirect. For example, normal offspring of hypercapnic subjects with COPD demonstrate significantly lower ventilatory and occlusion pressure responses to hypoxia and hypercapnia (~60% lower) than do normal offspring of eucapnic subjects with COPD.
The CO2 sensitivity of children who have retained CO2 because of upper airway obstruction resulting from hypertrophy of the adenoids and tonsils is depressed, even after the tonsils and adenoids have been removed. Asthmatic patients who have retained CO2 during an asthmatic attack also show persistently low ventilatory responses to CO2, even after recovery from the asthmatic episode. Moreover, subjects who have had asphyxial, near-fatal episodes of asthma display lower ventilatory and occlusion pressure responses to hypoxia than do either age-matched normal subjects or asthmatic subjects with no history of near-fatal episodes.
There is also a small group of subjects who retain CO2 even though lung function is normal. In some of these patients, the cause of the depressed CO2 sensitivity is not known, but in others it seems to be associated with specific diseases, certain metabolic abnormalities, such as alkalosis, or the long-term administration of respiratory depressant drugs, such as methadone. These conditions are summarized in Table 1. In a few conditions listed in Table 2, only the ventilatory response to hypoxia is depressed. Individuals with these conditions are able to maintain blood gas tensions within usual limits because of their normal CO2 drive. However, when CO2 sensitivity is reduced by the administration of drugs (e.g., premedication before surgery), significant hypoxemia can develop. Depressed ventilatory responses to hypoxia may also increase the tendency for CO2 retention to develop in COPD and may be a risk factor for acute mountain sickness.

TABLE 1. Conditions sometimes associated with depressed responses to hypercapnia and hypoxia

TABLE 2. Conditions associated mainly witha decreased response to hypoxia

Certain conditions seem to predispose to heightened responses to CO2 or hypoxia, even when the lungs are normal. These conditions are listed in Table 3.

TABLE 3. Conditions associated with increased responses to carbon dioxide and/or hypoxia

Abnormalities in mechanoreceptor function also can influence gas exchange. Patients with chronic airway obstruction who breathe with small tidal volumes tend to retain CO2, whereas those who breathe with larger tidal volumes do not. The small tidal volumes are caused by abbreviated inspiratory time and perhaps by heightened pulmonary or chest-wall receptor activity. Heightened mechanoreceptor activity may also be responsible for dyspnea in some patients with interstitial lung disease, as vagal blockade at times alleviates this sensation.

TESTS OF PERIPHERAL CHEMORECEPTORS

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The peripheral chemoreceptors also respond to CO2 and contribute about 20%–30% of the total ventilatory increase observed when CO2 is inhaled. Because peripheral chemoreceptors react rapidly to changes in CO2, peripheral chemoreceptor responses have been evaluated by measuring the immediate increase in ventilation caused by a few breaths of inspired CO2 or by measuring the immediate decrease in ventilation observed when CO2 is abruptly removed.
The response to hypoxia, like the response to hypercapnia, can be measured by either rebreathing or steady-state techniques. Because of the prominent effects of CO2 on breathing, it is important to keep the CO2 constant while the response to hypoxia is measured. Because O2 stores are small, the peripheral chemoreceptor response to O2 also can be evaluated by measuring the effect on ventilation of a few breaths of N2 or 100% O2.
No matter how it is measured, the ventilatory response to hypoxia is curvilinear, making quantitation difficult. The response can be made linear, however, by relating ventilation to the reciprocal of PO2 or to the arterial O2 saturation.
There are insufficient data to establish the range of normal values of the ventilatory response to hypoxia; however, available information indicates that it is closely related to the metabolic rate and is at least as variable as the CO2 response.
Prolonged periods of hypoxia, particularly early in life, are associated with depression of the chemoreceptor response to hypoxia. The ventilatory response to hypoxia is reduced in native residents of regions at high altitudes and in children with congenital cyanotic heart disease. The carotid body appears to be larger in native residents of high altitudes. The change in size may be caused by increased carotid body vascularity, which raises PO2 and decreases responsiveness.
In the newborn, hypoxia causes only a transient increase in ventilation, which then subsides to nearly prehypoxic levels. It has been recently appreciated that in adult humans, hypoxia lasting for as short a time as 5 minutes produces a gradual reduction in ventilation from its initial peak level.
The initial increase in ventilation is of course mediated by the carotid body. The subsequent decrease seems to represent a depressant effect of hypoxia on central respiratory neurons by hypoxia-induced increases in cerebral blood flow and probably the release of inhibitory neuromodulators, such as adenosine.
Lung disease or respiratory muscle weakness can depress ventilatory responses to chemical stimuli. The depressant effect seems to be greater for the response to CO2 than for the response to hypoxia. As a result of studies in which airway resistance was increased by requiring subjects to breathe through external resistance, either during inspiration or expiration, it was suggested that the inspiratory work of breathing at a given level of PCO2 is fixed, so that when the ratio of inspiratory muscle work to ventilation is increased by disease, ventilation decreases. The hypercapnia observed in severe obstructive lung disease was explained by the increase in flow-resistive work associated with chronic airway obstruction.
More recent studies have indicated that small increases in airway resistance have little effect on resting ventilation or CO2 response in normal subjects and may even heighten ventilation. The mechanisms responsible for the preservation of ventilation under these circumstances could include intrinsic properties of the respiratory muscles, increased inspiratory augmenting output from lung and chest-wall mechanoreceptors, readjustment in the sequence of contractions of the respiratory muscles so that mechanical advantage of the muscles and their coordination is improved, and increased inspiratory drive originating from the motor cortex. This last mechanism may depend on the conscious perception of changes in airway resistance. It is interesting that the ability to detect changes in airway resistance varies, decreasing with increasing airway resistance, and that it decreases further when airway obstruction is chronic than when it is acute.
Because mechanical changes may limit the ventilatory response to chemical stimuli, other methods of assessing the output of respiratory motor neurons have been devised. Two methods have been employed: measurement of occlusion pressure and EMG of the diaphragm. Neither is perfect, but both are useful under certain circumstances.
In the measurement of occlusion pressure, the force of contraction of the inspiratory muscles under quasi-isometric conditions is determined as follows: The airway is momentarily blocked at the beginning of inspiration, and the negative pressure developed during inspiration is measured. In conscious subjects, the reproducibility of the response is greater when the airways are occluded for just a fraction of a second. The occlusion pressure increases with hypercapnia and hypoxia and can be related to change in PCO2 and PO2 to estimate chemosensitivity.
Airway occlusion at FRC produces a no-flow state at the relaxed position of the respiratory system. The absence of air flow and prevention of significant volume change during inspiration prevent increases in airway resistance or decreases in compliance from affecting this index of respiratory output. In patients with mechanical abnormalities of the ventilatory pump caused by diseases of the lung or chest wall, occlusion pressure therefore more accurately reflects the neuromuscular drive to breathe than does ventilation.
Because the tensions developed by the inspiratory muscles theoretically depend on their initial length, the occlusion pressure in patients with lungs hyperinflated by disease may not reflect respiratory drive accurately. Increased FRC in animals reduces occlusion pressure responses. However, studies in conscious humans in whom FRC has been changed by altering body position show little effect on occlusion pressure, even when changes in FRC are fairly large (1000 mL). A conscious person apparently maintains constant muscle tension successfully, despite changes in initial muscle length, by altering neural output.
Measurement of the electrical activity of the diaphragm is probably the most direct way of evaluating respiratory neuronal output. This can be accomplished by passing a catheter containing electrodes down the esophagus and positioning the electrodes so that they straddle both surfaces of the diaphragm.
Various ways have been devised to quantitate diaphragmatic electrical activity measured this way. In the method most used currently, diaphragmatic activity is integrated over small intervals of time (100 to 200 ms), and the average activity per time limit is recorded (the so-called moving average). Electrical activity measured in this way depends on the exact positions of the electrodes in relation to the diaphragm during breathing, so that it is difficult to compare one individual with another. It is possible, however, to use this method to determine the effect of different therapeutic interventions in the same person.

TESTS OF CHEMORECEPTOR SENSITIVITY

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When lung function is normal, the sensitivity of the peripheral and central chemoreceptors to CO2 can be evaluated by measuring the ventilatory response to inspired CO2. In the conventional steady-state test, the inspired CO2 is increased in steps, and ventilation at each step is related to the change in PaCO2. Sensitivity to CO2 is determined from the slope of the line relating ventilation to CO2. Although the central chemoreceptors are readily accessible to CO2, the size of cerebral CO2 stores increases the time required for ventilation to reach a steady state when PCO2 changes. Usually, the inspired CO2 concentrations at each step must be maintained constant for 10 to 20 minutes to ensure equilibration. Relative rates of equilibration of PCO2 in arterial and brain venous blood (Fig. 9) indicate that PaCO2 reaches its steady-state level long before the venous PCO2. It is apparent from Fig. 9 that if ventilation, which closely tracks cerebral venous PCO2, is measured too soon, chemosensitivity will be underestimated.

FIG. 9. Changes of ventilation, PaCO2, and cerebral venous PaCO2 when inspired CO2 is changed.

When CO2 is rebreathed from a bag containing CO2 at the mixed venous level together with O2, arterial and venous blood equilibrate more rapidly. After a brief transition period, PCO2 at all sites in arterial, cerebral, and mixed venous blood and alveolar air rises at the same rate. Consequently, the rate of change of PCO2 in alveolar air can be used as an index of the rate of change in PCO2 in the central chemoreceptors. The exact length of the transition period depends on the size of the rebreathing bag. When the volume of the rebreathing bag is about the same as the vital capacity, chemosensitivity can be estimated by continuous recording of ventilation and PCO2 after 45 to 60 seconds of rebreathing. Measurements for wide variations in PCO2 can be obtained in a few minutes. Estimates obtained by this rebreathing method agree with those obtained by the more prolonged steady-state technique. However, the rebreathing tests measure CO2 sensitivity at much higher levels of PCO2 than are usually encountered. Moreover, differences have been noted between rebreathing and steady-state ventilatory response to CO2 when metabolic acidosis or alkalosis is present. With the steady-state technique, moderate alkalosis and acidosis produce larger changes in the position of the ventilatory response line but relatively small changes in its slopes, whereas the reverse is true in the rebreathing tests. The explanation for this difference is obscure, but it may be related to the different levels of PCO2 at which steady-state and rebreathing tests are performed.

The average ventilatory response to CO2 is about 2.5 L/min/mmHg in normal adult men. It is somewhat less in women than in men and tends to decline with advanced age. It varies greatly between individuals but is much more constant in repeated measurements from a single subject. Some of this variability is caused by differences in personality, genetic makeup, and body size, and it is reduced when the CO2 response is corrected for differences in vital capacity.

Cortical activity is known to affect the response to CO2. Ventilatory responses to CO2 measured with the subject's eyes open are greater than ventilatory responses to CO2 measured with the subject's eyes shut.

CONTROLLED SYSTEM EFFECTS ON REGULATION OF BREATHING

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The translation of the output of the inspiratory neurons to ventilation involves, as shown in Fig. 8, the successive transformation of nerve impulses to muscle electrical activity, muscle shortening, force, and then ventilation. Usually, moderate changes in the mechanical properties of the muscles or chest bellows have little or no effect on the resting blood gas tensions. Compensating effects by the chemoreceptor and mechanoreceptor reflexes, conscious adjustments, and the intrinsic force-velocity relationships of the muscles themselves allow the force of contraction to increase whenever the rate of contraction is slowed. In the presence of sufficiently severe chest disease, however, gas exchange is inadequate despite all efforts to compensate.

FIG. 8. Steps by which respiratory neural activity is translated into ventilation.

Even when the compensatory responses prove ultimately to be adequate, changes in mechanical conditions (or metabolic rate) cause a transient period in which gas exchange is disturbed and gas tensions are abnormal. The degree to which blood gas tensions deviate from normal in such situations depends on the volume and arrangement of the body stores of O2 and CO2.

CO2 is contained in the body in large amounts as gas in the lungs, but mainly in the form of bicarbonate and carbonate solutions in blood and tissues. O2, on the other hand, is stored in much smaller amounts in alveolar gas, in solution, and in combination with hemoglobin and myoglobin. Disturbances in gas exchange cause small changes in PCO2 because of the large size of the CO2 stores, but large changes in PO2.

Rates of change of PO2 and PCO2 depend not only on the volume of gas stores, but also on organization—that is, the way O2 and CO2 contained in different body tissue compartments are linked by the circulation, rates of perfusion, and metabolic rates in the various body compartments—and the ability of the tissues in each compartment to bind CO2 and O2.

The rate at which peripheral and central chemoreceptors respond to changes in inspired CO2 and O2 depends on the arrangement of the body gas stores. The small size of the arterial compartment and the high rate of carotid body blood flow allow peripheral chemoreceptors to respond quickly to changes in both O2 and CO2. The larger CO2 stores of the brain cause the central chemoreceptors to respond more slowly to changes in inspired CO2. This difference in response time of central and peripheral chemoreceptors has been used to distinguish the contribution of each receptor to the CO2 response.

RESPIRATORY SENSORY RECEPTORS

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The receptors of the lungs and airways are innervated through the vagi and superior laryngeal and trigeminal nerves, and respond, as in other hollow visceral structures, to irritation of the lining layers and changes in distending forces. The mechanoreceptors associated with the respiratory muscles are innervated by spinal nerves and, like those in other skeletal muscles, monitor changes in joint movement and in the length and tension of the muscle itself.
Pulmonary Receptors
There are basically three types of pulmonary receptors: stretch receptors in the smooth muscles of the airway, irritant receptors in the airway epithelium, and J (juxtacapillary) receptors situated in the lung interstitium.
Stretch Receptors
Stretch receptors are innervated by large myelinated fibers. As the lung is inflated, these receptors inhibit inspiration, promote expiration, and initiate the Hering-Breuer reflex. In animals, lung inflation cuts short inspiration and produces expiratory apnea; the duration of apnea is proportional to the degree of inflation.
Direct measurements of stretch-receptor activity indicate that stretch receptors in humans are excited by even small changes in lung volume during quiet breathing. In humans, however, unlike what occurs in animals, vagal blockade to abolish stretch-receptor input does not affect breathing frequency or tidal volume at rest. Vagal blockade in both humans and animals does, however, prevent the increase in breathing frequency that occurs when ventilation is stimulated by hypercapnia or hypoxia and tidal volume is larger.
In animals, stretch-receptor activity helps to preserve tidal volume whenever the usual movements of the lung are hindered by changes in airways resistance or respiratory system compliance. Anything that retards lung inflation diminishes inspiratory inhibitory stretch-receptor activity. Therefore, inspiration is prolonged and tidal volume tends to approach its usual level when the airway is obstructed or respiratory compliance is reduced, despite mechanical interference. When expiration is hindered and lung deflation slowed, increased stretch-receptor activity heightens the force of contraction of the expiratory muscles and also prolongs expiratory time. Both these stretch-receptor actions tend to prevent mechanical impediments to expiration from increasing end-expiratory volume and, as a consequence, decreasing the resting length of the inspiratory muscle. Stretch-receptor activity, by promoting full expiration, helps preserve inspiratory muscle function.
Although stretch receptors are not important in humans in shaping resting breathing patterns, they may help maintain tidal volume when breathing is stimulated or lung or chest-wall mechanical performance is impaired. The increase in breathing frequency caused by stretch-receptor activity in animals and during stimulated breathing in humans decreases the work of breathing of the respiratory muscles, conserving the energy that has to be expended to produce gas exchange. Although it is well-known that peripheral inputs from lung mechanoreceptors strongly affect the timing of respiratory motor activity, at the present time it is difficult to separate clearly the ventilatory effects of the pulmonary stretch-receptor afferents from those of other vagal sensory components (e.g., irritant and C-fiber afferents). However, changes in vagal afferent activity elicited by phasic lung volume changes seem to control predominantly the duration of inspiration, whereas tonic inputs predominantly affect the duration of expiration.
Irritant Receptors
Irritant receptors, like the stretch receptors, are innervated by myelinated fibers, whereas unmyelinated fibers supply the J receptors. Unlike the stretch receptors, both irritant and J receptors are rapid-adapting (within seconds). Neither irritant nor J receptors have a pattern of firing that is related to the phases of inspiration and expiration. Consequently, it is believed that neither receptor has an important influence in determining the pattern of breathing at rest.
Mechanical stimulation of the airways or the inhalation of potentially noxious agents (e.g., particulate matter, nitrogen dioxide, sulfur dioxide, ammonia, and antigens) seems to excite irritant receptors and produce airway constriction. Stimulation of irritant receptors augments the activity of the inspiratory neurons and, by interaction with the stretch receptors, promotes rapid, shallow breathing. This pattern of breathing, in combination with airway constriction, may limit penetration of dangerous agents into the lung and prevent them from reacting with the gas-exchanging surfaces.
The inspiratory augmenting effect of irritant-receptor excitation and the increase in breathing frequency it produces may help maintain ventilation in asthmatic patients, even when the work of breathing is massively increased.
Irritant receptors can be excited by traction on the airways and are stimulated if atelectasis reduces lung compliance. These receptors seem to cause augmented breathing and the large sighs that occur sporadically during normal breathing, and help to open collapsed areas of the lung. As a consequence, irritant receptors help maintain adequate gas exchange.
J Receptors
J receptors are stimulated by pulmonary interstitial edema, but they also can be activated by various chemical agents, such as histamine, halothane, and phenyldiguanide. Activation of the J receptors causes laryngeal closure and apnea, followed by rapid, shallow breathing. When pulmonary edema develops as a result of exercise, J receptors seem to depress the activity of the exercising limbs by a somatic reflex involving cingulate gyrus. J receptors, together with irritant receptors, may be responsible for the tachypnea seen in patients with pulmonary embolus, pulmonary edema, and pneumonia.
Laryngeal Receptors
Mechanoreceptors and chemoreceptors in the upper airway reflexively affect the level and pattern of breathing, motor outflow to the upper airway and chest-wall muscles, and airway tone. The best-studied of the upper airway receptors are the laryngeal receptors. In fact, all areas of the laryngeal mucosa and deeper structures contain sensory nerve endings. Several types of laryngeal receptors have been described: (1) pressure receptors, (2) “drive” receptors, and (3) cold receptors.
Pressure receptors, the most numerous of the laryngeal receptors, are activated by increases in negative (intraluminal less than extraluminal pressure) or positive transmural pressure. Pressure receptors fire in response to both dynamic and static pressure changes, and are slow-adapting. Approximately, two thirds of the pressure receptors respond to negative pressure; the remaining third respond to positive pressure. Approximately one half of laryngeal pressure receptors demonstrate a respiratory modulation in the absence of air flow in the isolated, bypassed upper airway, suggesting that they respond to laryngeal muscle shortening in response to descending motor drive. These so-called drive receptors fire primarily during inspiration. Their firing pattern is diminished by paralysis of the intrinsic muscles of the larynx.
Reflexes elicited by laryngeal pressure receptors tend to stabilize the upper airway, retard its tendency to collapse in response to subatmospheric pressure, and re-establish its patency following occlusion. Laryngeal pressure receptors reflexively activate upper airway muscles while inhibiting inspiratory muscles of the chest wall. Negative transmural airway pressure reflexes increase the activity of inspiratory upper airway muscles (e.g., genioglossus, sternohyoid, cricothyroid, levator alae nasi, posterior arytenoids), advance the onset of the upper airway-muscle EMG relative to that of the diaphragm, increase the duration of inspiration and expiration, and decrease the average rate of rise of diaphragmatic and inspiratory intercostal EMG activity. (Normally, activation of upper airway muscles occurs 50 to 100 ms before the outset of diaphragmatic activation.) Reflex responses to negative pressure in the upper airway mediated by pressure receptors may explain the greater tidal volume, expiratory time, and ventilation during nasal than in tracheostomy breathing in conscious animals and humans.
In contrast to pressure receptors, laryngeal cold receptors are silent near body temperature but are activated by decreases in laryngeal temperature to 34°C or below. When active, cold receptors demonstrate a phasic, inspiratory firing pattern and, in contrast to pressure receptors, appear to adapt rapidly. Cold receptors appear to be located superficially in the mucosa on the edge of the vocal cords near the arytenoid process. Increases in lower airway resistance elicited by laryngeal cooling may be mediated by these receptors.
Finally, mechanical or chemical irritation of the larynx (e.g., probe contact or application of acid) elicits cough, laryngeal closure, bronchoconstriction, an increase in tracheal production of mucus, and a decrease in heart rate and blood pressure. These reflex responses to laryngeal irritation suggest that laryngeal chemoreceptors and mechanoreceptors function to protect the lower airway from aspiration or inhalation of toxic fumes.
Of interest, reflex responses to laryngeal stimulation appear to be state-dependent and are qualitatively different during wakefulness and sleep. For example, in the dog, application of distilled water to the larynx during wakefulness consistently elicits cough and bronchoconstriction. In contrast, the same maneuver performed during REM sleep does not stimulate cough, but rather elicits apnea and bradycardia.
Chest-Wall Receptors
Three types of receptors in the chest wall—joint, tendon, and spindle receptors—signal changes in the force exerted by the respiratory muscles and movement of the chest wall. Specialized Ruffini receptors, as well as pacinian and Golgi organs, are present in joints. Joint-receptor activity, which can be consciously perceived, varies with the degree and rate of change of rib movement.
Inputs arising from muscular receptors, both proprioceptive (particularly muscle spindle) and nociceptor afferent (types III and IV) endings, influence the level and timing of respiratory activity. Proprioceptor afferents (chiefly from the intercostal and abdominal muscles) project to the phrenic motor neurons, where their effect is on firing rate only, and to medullary respiratory neurons in the DRG and NRA, where their predominant effect is on respiratory timing.
Tendon organs in the intercostal muscles and diaphragm monitor the force of muscle contraction and produce an inspiratory inhibitory effect. It was once thought that tendon organ activity was provoked only by unusual levels of muscle force, but it is now believed that tendon organs are stimulated by even small changes in force. Tendon organ input may be important in regulating both intercostal muscle and diaphragmatic contraction during breathing at rest.
Muscle spindles, which are abundant in the intercostal muscles but scarce in the diaphragm, are involved in several kinds of intercostal respiratory reflexes and also help coordinate breathing during changes in posture and speech.
Figure 7 shows schematically the operation of the spindle and its neural connections. Spindles are located on intrafusal muscle fibers aligned in parallel with extrafusal fibers, which move the ribs. Motor innervation of the extrafusal fibers originates in alpha motor neurons, whereas the intrafusal fibers receive motor innervation from gamma (fusimotor) motor neurons. Passive stretch of an intercostal spindle by lateral flexion of the trunk, for example, increases spindle afferent activity and activates a monosynaptic segmental reflex that causes contraction of the parent extrafusal fiber and restores the upright position. The spindles also can be stretched by an efferent fusimotor discharge, which causes contraction and shortening of the intrafusal fiber itself. Some fusimotor fibers fire phasically, so that their rate of discharge rises during inspiration and falls during expiration; other fusimotor fibers are tonically active. The cerebellum determines the balance between tonically and phasically active fusimotor fibers. Without phasic fusimotor activity, spindle discharge would decrease when the extrafusal fibers contract during inspiration. Simultaneous activation of fusimotor and alpha motor neurons causes the spindles to be under continuous stretch during inspiration and enhances the contribution made by the intercostal muscles to respiration. If inspiratory movements are impeded, afferent activity from a spindle innervated by a phasically active fusimotor fiber is enhanced, thus increasing inspiratory muscle force and helping to preserve tidal volume. Activity from lower intercostal muscle spindles, through an intersegmental spinal reflex, also enhances diaphragmatic contraction, allowing the diaphragm to contribute to the compensatory increase in muscle force that occurs when respiratory movements are hindered. In contrast, stretch of the intercostal spindles in the midthoracic region of the chest decreases the duration of inspiration and diminishes the force of inspiratory muscle contraction. This reflex may cut short ineffective inspirations. Ineffective inspirations sometimes are seen in the newborn when the negative intrathoracic pressure produced by powerful diaphragmatic contraction causes paradoxical inward movement of the flexible infant rib cage.

FIG. 7. Intercostal muscle spindle.

Of considerable importance, spindle afferents reach the highest level of the central nervous system, the sensorimotor cortex. Projection of spindle afferent activity to the cerebral cortex allows respiratory muscle length and tension to be sensed consciously and modulated with great precision, thereby allowing complex volitional acts to be performed (e.g., speaking, playing a wind instrument). Spindle afferent activity also likely contributes to the sense of breathlessness. It has been suggested that dyspnea occurs when spindle afferent activity is “high” relative to the intensity of central motor activity to the inspiratory muscles. This concept, which has been termed length-tension inappropriateness, explains the dyspnea that arises in the setting of lung diseases that increase inspiratory muscle load and impede muscle shortening. Of interest, the sense of breathlessness can be affected in patients with chronic obstructive pulmonary disease (COPD) by application of vibratory stimuli to the intercostal muscles, which changes spindle afferent activity. Dyspnea is ameliorated by vibratory stimuli applied in phase with muscle contraction and worsened when the vibratory stimulus is applied out of phase with muscle contraction.

Integration of Afferent Input

Although it is clear that afferent input to the medullary respiratory neurons from mechanoreceptors in the lungs, respiratory muscles, and cardiovascular and thermal regulatory systems (and even the exercising limbs) have significant effects on breathing, the precise manner in which these inputs are integrated is poorly understood. However, the changes in respiratory motor activity elicited by changes in these inputs are not stereotyped. The reflex responses to these inputs may affect the motor output to some respiratory muscles more than others. Pulmonary stretch-receptor input inhibits chest-wall muscle activity (i.e., diaphragm and external intercostal muscles) but increases the activity of the upper airway-dilating muscles (i.e., posterior cricoarytenoid) and the chest-wall expiratory muscles. Even more interesting, some receptors seem to have opposing effects on muscles that normally act as agonists. For example, stimulation of esophageal mechanoreceptors by balloon distension of the distal esophagus reflexively inhibits diaphragmatic activity, both costal and vertebral, but enhances external intercostal activity.

PERIPHERAL CHEMORECEPTORS

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Sensors in both the carotid body (innervated by the ninth cranial nerve) and the aortic body (innervated by the tenth cranial nerve) respond to hypoxia by increasing ventilation. If the carotid and aortic bodies are removed, hypoxia depresses breathing. In most species, the increase in ventilation with hypoxia is more a consequence of carotid than of aortic body activity. The carotid body also responds, to a limited extent, to changes in PCO2 and hydrogen ion concentration, and it appears to be particularly important in the immediate increase in ventilation seen in metabolic acidosis. However, the increase in peripheral chemoreceptor activity caused by CO2 appears to be inconsequential under hyperoxic conditions.
With decreases in PaO2, afferent fibers from the carotid body increase their discharge hyperbolically. Reduction in PO2 rather than in O2 content in the arterial blood is mainly responsible for the increasing activity. The biochemical and physiologic mechanism that allows the carotid body to respond to even relatively mild hypoxia has not been completely elucidated, but some details are known. Although blood flow in the carotid body is unusually high, so is the metabolic rate. Vascular shunts through the carotid body as well as its high metabolic rate may produce areas of hypoxia within the carotid body, even when the arterial blood is fully saturated with O2. Measurements of carotid body PO2 have shown some extremely low tensions, but the range of tensions is wide. Cytochrome enzymes within the carotid body may have an especially low affinity for O2, thus accounting for the sensitivity of the carotid body to changes in PO2. Although the primary function of the peripheral arterial chemoreceptors is to transduce changes in arterial PO2, PCO2, and/or hydrogen ion levels into nerve signals, there is no general agreement as to how this is accomplished, nor is it known whether all stimuli act through a common mechanism.
Ultrastructural studies of the carotid and aortic bodies demonstrate the presence of two distinct types of cells. Afferent nerve terminals from the carotid sinus nerve appose type I glomus cells, which contain abundant, dense, clear-cored synaptic vesicles, mitochondria, and conspicuous rough endoplasmic reticulum. The cytology of type II (sustentacular) cells resembles that of Schwann cells. They envelop the afferent terminal-glomus cell complex.
Whereas it was originally proposed that the afferent terminals are chemosensitive and that the type I cells function as modulatory interneurons, subsequent studies have suggested that the integrity of the glomus cells (type I and perhaps type II cells) is essential for the process of chemoreception. After the glomus cells are destroyed, nerve endings alone seem unable to respond to physiologic stimuli.
Glomus cells (type I cells) contain a variety of agents, including acetylcholine, norepinephrine, dopamine, and 5-hydroxytryptamine. Recent immunocytochemical studies also have shown the presence of at least three polypeptides in the carotid body of cats and rats (i.e., substance P, vasoactive intestinal polypeptide [VIP], and enkephalins), suggesting that neuropeptides may play important roles in the transmission of nerve signals. Substance P, a member of the tachykinin group of polypeptides, has been proposed as a general transmitter/modulator for primary afferent fibers sensing nociceptive stimuli. In addition, substance P enhances the discharge of carotid body preparations in vivo and in vitro. These excitatory effects of substance P are dose-dependent, seem to be slow in onset, and last several seconds after intracarotid administration. Hypoxic excitation of the carotid body is markedly attenuated by substance P antagonists. The mechanism(s) for sensing O2 in the carotid body remains unclear. However, hypoxia depolarizes type I cells and increases cytosolic calcium, perhaps through effects on O2-sensitive, voltage-gated potassium channels and cytochrome protein(s) with a low affinity for O2. Depolarization of glomus cells in turn causes neurotransmitter release and activation of sinus nerve afferent terminals.
Efferent discharge to the carotid body from the CNS depresses afferent activity provoked by hypoxia. This efferent inhibition may prevent saturation of the carotid body response, allowing the carotid body to respond to a wider range of PO2 than it could otherwise. In part, efferent control depends on sympathetic nervous regulation of carotid body blood flow. However, other inhibitory efferent fibers that have no effect on the carotid body vasculature are also present.
With hypoxia, ventilation, like carotid body activity, increases hyperbolically (Fig. 6). Also, changes in PCO2 seem to enhance the ventilatory response to hypoxia, and vice versa (i.e., CO2 and hypoxia interact multiplicatively). Single carotid body fibers respond to both CO2 and hypoxia, so that some of the interaction of hypoxia and hypercapnia occurs at the cellular level in the sensor itself. However, other evidence suggests that convergence of input from central and peripheral chemoreceptors at the level of the CNS helps enhance the interaction of hypoxia and hypercapnia as ventilatory stimulants. Experimental studies on the effect of carotid nerve stimulation in different phases of breathing show that carotid body discharge is more effective in stimulating breathing during inspiration than during expiration. Carotid body discharge varies spontaneously during the breathing cycle as a result of variations in PaO2. The relationship between oscillations in carotid body activity and phase of breathing depends on the circulation time between the lungs and the carotid body. Thus, changes in cardiac output theoretically might affect both the level and pattern of breathing. When central chemoreceptor activity and the response to CO2 have been eliminated by destruction of the ventrolateral medullary surfaces, input from the carotid body alone is sufficient to maintain rhythmic breathing. Both central and peripheral chemoreceptors respond proportionally as the level of PCO2 is altered. Some studies suggest that increases in the rate of change of CO2 but not in the rate of change of PO2 also stimulate the carotid body.

FIG. 6. Effect of changing PaCO2 on (A) the ventilatory response to hypoxia and (B) the ventilatory response to hypercapnia.

CENTRAL CHEMORECEPTORS

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When CO2-enriched gas is inspired, ventilation increases. The increase in ventilation tends to minimize the rise in PaCO2. Because the amount of CO2 delivered to the chemoreceptors depends on the CO2 carried to them by the arterial blood, the PaCO2 determines the PCO2 in the immediate environment of the chemoreceptors.
The effect of increases in ventilation on PaCO2 can be determined by the following equation:

where

CO2 is the metabolic production of CO2 each minute,

A is the alveolar ventilation, PICO2 is the partial pressure of inspired CO2, and K is a proportionality constant.

It can be seen that the greater the increase in ventilation caused by a change in PICO2, the lower is the PaCO2. In conscious humans, central chemoreceptors located within the medulla account for 70%–80% of the increase in ventilation. The peripheral chemoreceptors account for the remainder of the increase in ventilation when CO2-enriched gas is inspired and for all the increase in ventilation produced by hypoxia.

The exact location of the central chemoreceptors is still disputed, although most experimental data indicate that they (1) are distinct from the inspiratory motor neurons themselves, (2) are not located in the dorsal and ventral groups described earlier, and (3) respond to changes in hydrogen ion concentration of brain interstitial fluid but also may respond directly to changes in PCO2 (perhaps through a change in intracellular pH).

Studies in which drugs and temperature probes have been applied to the ventrolateral surface of the medulla have demonstrated abrupt and striking ventilatory effects, suggesting that many of the neurons comprising the central chemoreceptors or their associated axons may be located near the surface. Chemoreceptor activity can be influenced from three different superficial areas (Fig. 4). Recent studies suggest that respiratory cells near the ventral surface are intermingled with cells that also have significant vasomotor effects. Many agents that increase ventilation when applied superficially to the ventral medullary surface (e.g., nicotine, acetylcholine, kainic acid) also raise blood pressure. On the other hand, agents that decrease respiration when similarly applied (e.g., t-amino butyric acid, taurine, enkephalins) also decrease blood pressure. Nonetheless, discrete areas have been described from which either respiratory or vasomotor effects predominate (e.g., the nucleus paragigantocellularis, a collection of cells close to the ventral medulla).

FIG. 4. Ventrolateral medulla and its rostral (R), intermediate (I), and caudal (C) chemosensitive areas.

The crucial experiments in which activity from the central chemoreceptors would be directly recorded have never been performed. Hence, it has been possible to evaluate central chemoreceptor activity only indirectly. This is usually accomplished by measuring the increase in ventilation or phrenic nerve activity produced when the PICO2 is changed. Changes in ventilation theoretically should be related to changes in hydrogen ion concentration in the brain, but this concentration cannot be measured easily, either in humans or in animals. Instead, changes in ventilation are conventionally related to the measured levels of PaCO2. This kind of indirect estimation of central chemoreceptor activity is valid only under restricted circumstances and only if certain assumptions are made. It is assumed, for example, that in a steady state, after CO2 has been inspired for 10 to 20 minutes, changes in PaCO2 reflect changes in the hydrogen ion concentration of the brain. By the Henderson-Hasselbalch equation, hydrogen ion concentration in the brain, as in other tissues, varies according to the ratio PCO2/ HCO–3, where PCO2 is the partial pressure of CO2 at the chemoreceptor in the interstitial fluid and HCO–3 is the bicarbonate concentration of the medullary interstitial fluid. Hence, increases in bicarbonate concentration decrease hydrogen ion concentration, whereas decreases in bicarbonate concentration have the opposite effect.

The relationship between arterial PCO2 and PCO2 in the brain interstitial fluid depends on cerebral venous PCO2 and therefore on cerebral blood flow. The greater the cerebral blood flow, the smaller the difference between PCO2 in arterial blood and in interstitial fluid. As cerebral blood flow increases with PCO2, the change in ventilation produced by a change in PaCO2 depends on the CO2 responsiveness of cerebral blood vessels as well as on the sensitivity of the central chemoreceptors. This may be a significant factor in patients with cerebrovascular disease.

Changes in blood bicarbonate levels are not immediately mirrored in the brain interstitial fluid. In addition, evidence suggests that hydrogen ion concentration in interstitial fluid is actively regulated by cellular pumps at the blood-brain barrier or by the metabolism of brain cells. This means that in metabolic acidosis or alkalosis, neither PaCO2 nor hydrogen ion concentration in blood may reliably indicate the status of hydrogen or bicarbonate ion concentrations in interstitial fluid.

The stimulatory effect of acid injected into the blood on the peripheral chemoreceptors lowers PCO2. Because the transfer of PCO2 between blood and brain interstitial fluid is faster than the transfer of hydrogen or bicarbonate ions, the brain interstitial fluid may actually become alkaline when the blood PCO2 is acutely made acidic. Direct administration of acid into the cerebrospinal fluid to bypass the blood-brain barrier increases the hydrogen ion concentration in brain interstitial fluid and drives the PaCO2 down by stimulating central chemoreceptors.

With chronic acid-base disturbances, hydrogen ion changes in cerebrospinal fluid are usually qualitatively the same as those in the blood but are quantitatively less.

The effect of chronic metabolic acidosis and alkalosis on ventilatory responses to CO2 is shown in Fig. 5. It can be seen that in metabolic acidosis the level of ventilation is greater at any given level of PCO2, whereas in metabolic alkalosis ventilation decreases. These changes in ventilation reflect the altered level of bicarbonate in the brain interstitial fluid. If the same ventilation results are plotted as a function of hydrogen ion concentration in brain interstitial fluid, the response lines are identical.

FIG. 5. Effect of changes in blood bicarbonate on the relationship between ventilation and PCO2. The asterisk indicates the response line at the usual level of HCO–3.

In humans and animals, increases in PCO2 over a wide range cause a virtually linear increase in ventilation. At levels of PaCO2 >80 to 100 mmHg, the response to hypercapnia diminishes and may plateau. Decreases in PaCO2 below the usual level depress ventilation. In anesthetized and sleeping animals and humans, artificial hyperventilation with progressively reduced PCO2 eventually produces apnea. In a normal, awake human, however, active voluntary hyperventilation rarely causes apnea. In most cases, when voluntary hyperventilation is suspended, the increase in ventilation persists for perhaps 30 to 50 seconds. The persistence of ventilation in awake subjects at low levels of PCO2 has been attributed to a “wakefulness drive” caused by the continued impingement of other stimuli (e.g., noise, mechanoreceptor input, and light input) on the respiratory neurons. However, continuation of phrenic nerve activity at low levels of PCO2 has been described even in anesthetized animals made to hyperventilate actively by electrical stimulation of the carotid body nerves. This effect, which has been attributed to persisting reverberations in medullary respiratory neuron circuits, probably contributes to the wakefulness drive and helps stabilize breathing.

PATTERN OF MOTOR OUTFLOW TO THE INSPIRATORY MUSCLES

2014-02-19T19:55:00.000-08:00

The firing of the bulbospinal inspiratory neurons projecting to the diaphragm and intercostal muscles increases progressively throughout inspiration and is terminated abruptly (off-switching). The ramplike increase in activity of these bulbospinal neurons (the central inspiratory activity) causes a progressive increase in excitation of the inspiratory muscles and hence their force of contraction (Fig. 2). The electrical and mechanical analogues of central inspiratory activity are, respectively, the integrated activity of the phrenic neurogram and diaphragmatic electromyogram (EMG) and the pleural pressure waveform. The progressively augmenting shape of central inspiratory activity allows the inspiratory musculature to overcome the progressive increase in elastic recoil of the lung during inspiration despite progressive shortening and a decrease in the intrinsic ability of the inspiratory muscles to generate force (i.e., the length-tension relationship).

FIG. 2. Effect of hypercapnia on the duration of the phrenic nerve electrical activity integrated as a moving time average and its rate of increase and the pleural pressure waveform. Note the similarity in shape of the integrated phrenic neurogram and the pleural pressure tracing. Following bilateral vagotomy, the duration of inspiration remains relatively constant despite the progressive increase in PCO2.

Control of the rate of rise in central inspiratory activity and hence the rate of lung inflation differs from control of inspiratory off-switching. Both chemical (e.g., hypoxia and hypercapnia) and nonchemical (e.g., thermal and mechanoreceptor afferents) inputs affect the steepness of the ramp of central inspiratory activity. On the other hand, the timing of inspiratory off-switching depends largely on inputs from pulmonary stretch receptors and from higher CNS structures, such as the NPBM and the KFN.

In anesthetized animals, phasic increases in lung volume resulting from the ramp of central inspiratory activity progressively increase pulmonary stretch-receptor activity. Integration of inputs from pulmonary stretch receptors and projections reflecting the intensity of the central inspiratory activity by as yet incompletely described pools of neurons terminates inspiration. Vagotomy eliminates stretch-receptor input, prolonging inspiration and increasing tidal volume, but the rate of rise in central inspiratory activity and hence the rate of inspiratory air flow are virtually unchanged. On the other hand, hypoxia and hypercapnia increase the steepness of the ramp of inspiratory activity and hence increase the rate of inspiratory air flow and tidal volume, but they have little effect on the duration of inspiration and frequency of breathing.

When the vagus is intact, so that respiratory neurons receive input from the stretch receptors as well as inputs reflecting central inspiratory activity, the duration of inspiration is reduced, because the inspiratory off-switch is activated earlier. Because central inspiratory activity increases with time, more stretch-receptor input (i.e., a greater change in lung volume) is needed early in inspiration to terminate a breath. This accounts for the curvilinear relationship between tidal volume (Vt) and inspiratory time (tinsp) that has been noted in studies of anesthetized animals (Fig. 3).

FIG. 3. Effect of lung volume information in determining off-switch and, hence, tinsp. Vagal input allows the off-switch threshold to be reached earlier in inspiration. The numbers refer to the PCO2 with the vagi intact. Inspiratory time declines and tidal volume rises with increasing hypercapnia. Without lung volume information (vagotomy), tinsp is fixed.

Consistent with these observations is the idea that ventilatory responses to hypercapnia and hypoxia depend on the sensitivity of both stretch receptors and chemoreceptors. Chemoreceptor sensitivity, because it influences the rate of increase in central inspiratory activity, is more closely related to the average level of air flow during inspiration than to minute ventilation. That is, the change in the ratio of tidal volume to inspiratory time, rather than the change in ventilation itself, most closely reflects chemical drive. On the other hand, the change in inspiratory time as a fraction of total breath duration indicates the activity of stretch receptors.

Although ventilation is conventionally thought to be equal to tidal volume times frequency (f), the concept of central respiratory neuronal organization suggests that ventilation should more realistically be considered to be the product of the following:

where tinsp is inspiratory time and texp is expiratory time.

Some studies in humans have tried to separate neural and chemical responses to hypoxia and hypercapnia by analyzing ventilatory responses with this approach. In some cases, depressed ventilatory responses to CO2 seem to be caused by altered mechanoreceptor function rather than by depressed chemosensitivity.

It is important to remember that this concept originated from experiments carried out in anesthetized animals and accordingly does not include the effects on breathing of inputs eliminated by anesthesia. These additional inputs, occurring during both wakefulness and sleep, may greatly distort the basic relationships between the medullary respiratory neurons observed in animals during anesthesia. Thus, in awake humans, increases in breathing frequency produced by hypercapnia and hypoxia are associated mainly with a shortening of expiratory time, whereas inspiratory time remains relatively constant. Rapid-eye-movement (REM) sleep is associated with an irregular breathing pattern and seems to eliminate ventilatory increases to hypercapnia, but not to hypoxia. In non-REM sleep, breathing is more regular, but responses to changes in CO2 remain lower than during wakefulness.

Even in anesthetized animals, influences from thermal and circulatory receptors can affect breathing. For example, temperature increases accelerate the frequency of breathing without changing tidal volume.

Timing Of Respiratory Motor Activity

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During inspiration, firing rates increase monotonically in both inspiratory propriobulbar and bulbospinal neurons. Early in expiration, inspiratory propriobulbar neurons are silenced, but the activity of inspiratory bulbospinal neurons stops only momentarily, reappearing after a brief period of silence and then gradually declining as expiration proceeds. This PIIA corresponds in time to the period of firing of early-expiratory neurons in the DRG and VRG. Expiratory bulbospinal neurons are silent during this early phase of expiration, whereas inspiratory propriobulbar neurons are actively inhibited. Furthermore, because the time course of inhibition of the respiratory propriobulbar neurons is similar to the time course of activity of the early-expiratory units, it has been suggested that the respiratory rhythm is caused by inhibition of an inspiratory ramp generator by these early-expiratory neurons.
Based on these observations, it has been proposed that expiration be divided into two phases, EI and EII. The EI phase corresponds to the period of PIIA, whereas the EII phase corresponds to the period in which PIIA is absent and expiratory neuronal activity may be present. In some situations, PIIA may extend throughout expiration, suggesting that the respiratory rhythm does not depend on the occurrence of activity in expiratory neurons.
PIIA appears to be associated with “braking” of expiratory air flow by contraction of the inspiratory muscles. Increases in PIIA and prolongations in EI occur, for example, when the larynx is bypassed so as to decrease upper airway resistance. PIIA (EI) is markedly reduced or eliminated by vagotomy, suggesting that mechanoreceptors that sense lung volume and/or tracheal air flow are important inputs. Hypercapnia decreases the duration of EI, whereas hypoxia appears to do the reverse. Increases in PIIA may contribute to the increase in functional residual capacity (FRC) observed during hypoxia.
Respiratory timing can be significantly affected by the rostral pontine pneumotaxic center, which comprises the NPBM and KFN. This structure contains a number of neurons that have different patterns of firing: inspiratory, expiratory, or phase-spanning. When the vagi are intact, discharge patterns in the NPBM are mainly tonic, but they become more clearly phasic after vagotomy. Both the VRG and the DRG send projections to the pneumotaxic center, so that the respiratory activity seen in this center appears to be of medullary origin. Depending on the region involved, stimulation of the pneumotaxic center can either terminate or prolong inspiration. Stimulation of the dorsolateral region terminates inspiration. The earlier in inspiration the stimulation is applied, the stronger is the stimulus needed. If the pneumotaxic center is lesioned and the vagi are cut, an apneustic breathing pattern develops in anesthetized animals that is characterized by prolonged inspiratory time. If time is allowed for recovery, however, and the animal regains consciousness, breathing loses its apneustic quality. If the animal is then given anesthesia or allowed to go to sleep, the apneustic pattern returns. These observations suggest the lack of importance of the pneumotaxic center in generating the respiratory pattern, and indicate that an interaction between states of alertness and the activity of higher brain centers and the brain stem bulbopontine respiratory neurons can significantly affect respiratory rhythm.
It is not clear whether some or any of the different respiratory neurons described in fact make up the central pattern generator. Three different ways in which the central respiratory pattern may be produced in the brain have been proposed. In one, the pattern generator is composed only of inspiratory neurons; an inspiratory ramp continues until it is terminated by the activity of off-switch neurons. The off-switch neurons are triggered after some predetermined time or after the inspiratory ramp reaches some threshold level of activity. Both trigger and ramp neurons could be stimulated by hypoxia and hypercapnia. In this scheme, inspiration is a self-terminating process carried out by cells whose activity is confined to inspiration.
In a second hypothesis, the central pattern generator may include both inspiratory and expiratory cells affected by chemical drives causing tonic increases in the activity of each. The increasing ramplike discharge seen in inspiratory intercostal and phrenic nerves may result from a gradual decline in inhibition rather than a gradual increase in excitation. This hypothesis is based on the observation that during apnea induced by hypocapnia, decreases in PO2 elicit inspiratory tonic activity. Progressive decreases in PO2 during apnea elicit progressive increases in tonic inspiratory activity until at a critical level of hypoxia the respiratory rhythm reappears. On the other hand, hypocapnia under hyperoxic conditions produces continuous firing of expiratory neurons, which increases as PCO2 rises until rhythmic breathing resumes. This suggests hypoxia exerts an excitatory effect predominantly on inspiratory activity, and that hypercapnia affects expiratory motor activity.
The third idea is that respiratory rhythmogenesis arises in the antagonistic activity of inspiratory and early-expiratory neurons and does not depend on the activity of conventional expiratory neurons that peaks late in the expiratory phase.

Interrelationship Between Dorsal and Ventral Respiratory Groups

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The precise interactions between the DRG and VRG remain unclear. Earlier studies indicated that inspiratory neurons of the DRG projected to the VRG, but a reciprocal connection was not apparent. These studies suggested that the central pattern generator was composed only of inspiratory cells and was located in the DRG. In this view, the DRG was the prime mover in the genesis of the respiratory rhythm, dominating the cells in the VRG and governing their activity. More recent studies indicate that cells from the VRG (Bötzinger complex) may inhibit inspiratory neurons in the DRG. Ablation experiments eliminating either the entire DRG or the Bötzinger complex in the VRG do not eliminate rhythmogenesis, indicating that substantial redundancy is present in the system.
The functional significance of the interconnections between groups of inspiratory cells in the DRG and VRG is also unclear. These interconnections may serve to synchronize the timing of neuronal firing in anatomically separate locations. For example, midline incisions through the medulla are associated with asynchronous firing of the two phrenic nerves.

Ventral Respiratory Group

2014-02-19T19:47:00.005-08:00

The VRG in the medulla comprises several anatomically and probably functionally distinct populations (Fig. 1). One classification divides the neurons of the VRG into three aggregates: the nucleus retroambigualis (NRA), the nucleus para-ambigualis (NPA), and the nucleus retrofacialis (NRF).
The nucleus ambigualis (NA) is composed primarily of subnuclei of motor neurons innervating the laryngeal, pharyngeal, and facial muscles. This nucleus also contains the vagal motor neurons innervating the bronchial smooth muscles and the smooth muscles of the thoracic and abdominal viscera. These neurons are almost completely inactive during deep anesthesia, suggesting that they are not essential to respiratory rhythmogenesis.
The NPA is located in the region medial to the NA and 1 mm caudal to 3.5 mm rostral to the obex. The NPA is composed primarily of premotor inspiratory neurons, but some expiratory cells are present.
Most of the inspiratory neurons of the NPA (like Ia cells in the DRG) fire in a ramplike fashion, with peak activity occurring at the conclusion of the inspiratory phase. The NPA also contains a few inspiratory propriobulbar, so-called early-burst neurons. These cells begin to discharge slightly before the onset of the phrenic discharge, peak rapidly, and then demonstrate a decline and disappearance of activity in the latter half of inspiration. They send no projections to spinal motor neurons, but they have a rich pattern of arborization with expiratory neurons in the contralateral NRA, whose activity they appear to inhibit.
The activity of other neurons in the VRG (located in the NRA and NRF) is mainly directed to expiration. The expiratory neurons in the NRA demonstrate a slowly augmenting pattern of activity, with peak discharge late in expiration. Input from pulmonary stretch receptors prolongs the time of firing of these neurons. Hypercapnia causes these neurons to discharge earlier in inspiration and increases the steepness with which their rate of discharge rises. Lesioning experiments indicate that neurons in the NRA are the sole source of expiratory premotor neurons but are not of fundamental importance in generating the respiratory rhythm.
Respiratory neurons in the NRF (also called the Bötzinger complex) and in an area immediately rostral to it, called the pre-Bötzinger complex, have been described. Bötzinger neurons discharge mainly in expiration with a slowly augmenting firing pattern that peaks at end-expiration. They send projections to the DRG on the opposite side and seem to inhibit the inspiratory neurons located there. On the other hand, pre-Bötzinger neurons fire during inspiration, demonstrate pacemaker-like activity, and appear to be exclusively propriobulbar in type. In the neonatal rat, lesions in this pre-Bötzinger complex eliminate respiratory rhythmogenesis. Some pharyngeal motor neurons also can be found in the NRF.

Fig. 1

Medullary Respiratory Neurons

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The respiratory neurons in the medulla seem to be aggregated into two groups (Fig. 1). One collection, the ventral respiratory group (VRG), forms a longitudinal column of neurons in the ventrolateral part of the medulla. It extends rostrally from the upper border of the spinal cord almost to the bulbopontine boundary. The other group, the dorsal respiratory group (DRG), is more circumscribed anatomically. It is located in a more medial and dorsal part of the medulla in the region of the ventrolateral nucleus of the tractus solitarius (NTS) and extends from the obex about 2.5 mm rostrally.

FIG. 1. Schematic depicting the organization of medullary respiratory neurons in the dorsal and ventral respiratory groups (DRG and VRG, respectively). Structures on one side only are shown. Axons from inspiratory bulbospinal neurons in the nucleus tractus solitarius (NTS) and the nucleus para-ambigualis (NPA) decussate rostral to the obex and extens caudally in the contralateral cord. Axons from expiratory bulbospinal neurons in the nucleus retroambigualis (NRA) decussate caudal to the obex. Bötz = Bötzinger complex in the nucleus retrofacialis; NA = nucleus ambigualis.

The nuclei of the solitary tract appear to function as relay stations for important respiratory and cardiovascular information. Afferents from pulmonary stretch receptors and carotid chemoreceptors and baroreceptors appear to synapse for the first time in the brain at this location.

Ventilation

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The respiratory system, along with cardiovascular structures, operates as part of an intricate organization controlled by the central nervous system (CNS) to ensure optimal cell performance, providing sufficient oxygen to meet metabolic requirements and removing enough carbon dioxide so that cell function is not impaired by excessive changes in hydrogen ion concentration. The major function of the respiratory system is to maintain the arterial tension of oxygen (PaO2) and carbon dioxide (PaCO2) within acceptable limits in the face of changing metabolic needs and environmental conditions. To achieve this, the system is equipped with multiple sensors that monitor changes in blood chemistry (chemoreceptors) and changes in the mechanical properties of the lung and chest wall (mechanoreceptors). The chemoreceptors and mechanoreceptors allow ventilation to be continuously readjusted in accordance with metabolic needs, despite changes in body posture that alter the mechanical advantage or movement of the respiratory muscles. In addition, these receptors coordinate the contraction and relaxation of the respiratory muscles, so that adequate gas exchange is carried out with minimum expenditure of energy.
In addition, the respiratory chemoreceptors and mechanoreceptors participate in a protective network that adjusts the pattern of breathing and the mechanical conditions of the airways to minimize the deleterious effects on the lung of inhaled, noxious material.
Ventilation, unlike blood pressure and cardiac output, can be controlled consciously (voluntarily) as well as automatically (involuntarily). Indeed, the pathways for voluntary and automatic control of the respiratory muscles are anatomically separate. Voluntary as well as automatic control is essential for using the respiratory muscles in speech. In humans, afferent information continuously fed back to the CNS by mechanoreceptors in the airways, lungs, and chest wall allows the force of contraction of the respiratory muscles to be coordinated smoothly in volitional acts.
Besides inputs from respiratory system sensors, ventilation is influenced by projections from the vasomotor neurons to respiratory neurons and by signals received from thermoreceptors and vascular receptors. The multiplicity of inputs to the respiratory neurons ensures that ventilation is maintained when disease affects one or more afferent pathways or when the perception of some sensory cue is blunted by a depressed state of consciousness (e.g., sleep or anesthesia). However, conflicting demands and signals from different receptors may be responsible for dyspnea, a common symptom in respiratory disease.

Normal Lung X

2013-11-06T05:19:00.000-08:00

RESPIRATORY TRACT DEFENSE MECHANISMS
For the exchange of gases, conditioning of inspired air, and defense against inhaled toxicants to be accomplished simultaneously, highly synergistic interactions between respiratory tract clearance and secretion and biochemical and cellular defense mechanisms are required. In the normal lung, defense functions are mediated by epithelial cells of the airways and alveolar regions, resident alveolar macrophages, and numerous proteins in the extracellular spaces and mucous lining layers. Resident lung macrophages carry out the normal tasks of lung defense by selective phagocytosis of foreign particles; secretion of proteases, oxygen free radicals, and cytokines; and antigen presentation. In the presence of toxicants or other pathologic conditions, infiltration of bloodborne phagocytes, such as neutrophils, and toxicant-specific immunologic mechanisms, such as antibody production by B lymphocytes and cellular cytotoxic actions by T lymphocytes, augment the normal defense functions. Inflammatory cells recruited into the lungs tend to produce indiscriminate injury to resident lung cells and tissues by nonselective release of proteases, oxygen free radicals, and other cytotoxic agents. The lung appears to be designed to clear normal levels of inhaled pollutants without activating these inflammatory patterns, but it can activate them when more severely stressed.
Deposition of Inhaled Gaseous Toxicants
Because the physical mechanisms of transport and chemical uptake vary significantly between different airborne toxicants, no single approach can be used to estimate the pulmonary uptake of all inhaled agents. For instance, formaldehyde and ozone are both highly reactive gaseous toxicants with an inspiratory uptake of greater than 90%. However, the solubility of formaldehyde in aqueous biologic solutions is approximately 12 times greater than that of ozone. Because of their different solubilities, the critical target sites of injury for formaldehyde and ozone are at opposite ends of the respiratory tract. The major sites of uptake and toxic reactions of formaldehyde are in the nose and other parts of the upper respiratory tract. The uptake of formaldehyde in the upper respiratory tract is so rapid that virtually none of it reaches the lower respiratory tract. In contrast, because of the lower solubility of ozone, more of it reaches the lower respiratory tract. Significant uptake of ozone does occur in the nasal passages and upper respiratory tract; however, this uptake is associated with reaction of ozone with components of the thick mucous layer lining this region. The site of greatest injury from inhalation of ozone, and similar oxidant gases, is the alveolar epithelium at the transition between airways and the gas exchange region. In this region, the surface lining fluids are thin, so that the probability of ozone reacting directly with the underlying alveolar epithelial cells is greater. The critical respiratory targets and the toxic responses to all airborne pollutants depend on their inhaled concentrations, the resulting concentration gradient in different regions of the respiratory tract, and the effects of scrubbing and/or detoxification of the reactive gas by the mucous lining layer overlying the epithelial layer in each region.
Deposition of Inhaled Particles
The alveolar septal region is continually bombarded by a variety of organic and inorganic materials ranging from transition metals to animal and human proteins. Although the upper respiratory tract and upper airways filter most inhaled particulate matter, it is well documented that particles of 1 µm in size are not effectively filtered by the upper respiratory tract and that a significant fraction of these particles deposit on the intrapulmonary airways or reach the alveolar region. Normal ambient air can contain on the order of 10,000 respirable particles, defined as less than 10 µm in size with a mass median aerodynamic diameter (MMAD) of 0.3 µm, per cubic centimeter. Up to 30% of these particles deposit on medium and small airways, and about 10% deposit in the alveolar region. Thus, if a minute ventilation of 10 L is assumed, 30 million particles deposit per minute on smaller airways and 10 million particles deposit per minute on alveoli and alveolar ducts. Although the human lung contains 500 million alveoli, the particles tend to deposit proximally, and the load can be estimated to be up to one particle per minute per alveolus in the proximal alveolar ducts. The lung handles this steady, normal load of particulate matter without inducing inflammatory amplification.
These same pollutants would cause a strong inflammatory reaction if injected into another organ, yet they appear to cause virtually no reaction in alveolar septa in normal lungs. This is remarkable when one considers that the alveolar-capillary gas exchange membrane in most regions is thinner than 1 µm. If the organic and inorganic materials reaching the airways and alveolar surface were to stimulate the type of inflammatory reactions that occur in many other tissues, white cells would be rapidly recruited into these spaces and a progressive inflammation would result, leading to acute bronchitis, acute alveolitis, and/or interstitial fibrosis. The absence of an injurious response to normal lung particle burdens appears to be the result, in part, of the unique role of resident lung defense cells, such as alveolar macrophages. Each alveolus contains an average of 12 macrophages, which are thought to process all particles reaching this region under normal conditions. Alveolar macrophages have been shown to have a blunted capacity for antigen presentation and mitogen production compared with other monocytic phagocytes, and thus they are able to process inhaled particles without stimulating excessive immunologic responses or lung inflammation. The lipids and/or proteins of the alveolar surface lining layer have been shown to have anti-inflammatory actions. High particle loads given experimentally have been shown to overload these and other anti-inflammatory defense mechanisms and induce alveolar inflammation. The dose-response relationship for the onset of particle-induced inflammation is not known, nor are the mechanisms controlling this process.
Pulmonary disorders in which particle deposition and/or clearance plays a major role include hypersensitivity pneumonitis, silicosis, asbestosis and other mineral fiber disorders, and a number of metal- and organic antigen-specific disorders. In most of these cases, the biologic association between toxicant dose and health effects has been clearly demonstrated.
Epidemiologic studies demonstrate a significant association between particulate exposure and increases in hospital admissions, morbidity, and mortality. Children, whose small airways are potentially more susceptible to particle-induced inflammation and limitations of air flow, are thought to be at high risk. Airborne particulate levels as low as 150 µg/m3 are statistically associated with increases in elementary school absenteeism. The association between particle concentration and increased mortality appears to be maximal when the experimental results are averaged over a 3- to 5-day period. Such studies have been the primary means of identifying human health risks associated with particle inhalation. These studies taken as a whole suggest that ambient levels of particles on the order of 100 µg/m3 are associated with adverse health effects. Each increase of 10 µg/m3 in the PM10 (particulate matter with an aerodynamic diameter of 10 µm) is associated with an approximate 1% increase in mortality. The increased mortality appears to occur largely among the sick and elderly. The underlying biologic mechanisms responsible for these epidemiologic associations have not been determined. Interactions between particles and other pollutants, such as sulfur dioxide and nitrogen dioxide, and the effects of climate have been suggested as critical factors. High levels of trace metals in the particulate matter from urban and industrial sources have been suggested as possible causative agents. Table 6 illustrates the significant differences that exist in trace element composition between air sampled at a remote natural site and in various North American cities. In cities with a large number of anthropogenic sources, the potentially toxic trace elements of nickel, copper, and zinc are present at substantial levels. Particle samples from natural sites that are not contaminated by anthropogenic sources do not contain significant levels of these elements.

TABLE 6. Comparison of ambient dust concentrations

Deposition of inhaled particles occurs according to physical mechanisms of inertial impaction, gravitational sedimentation, diffusion, and interception. A variety of factors, such as aerosol particle size, density, shape, hygroscopic/hydrophobic character, and electrostatic charge, may also play important roles in determining how these mechanisms control the location and efficiency of deposition in the lungs. Because particles are present in a range of sizes and shapes, an aerosol is typically described by a size distribution or a mass/count weighted mean. In toxicologic evaluations, the Mass Median Aerodynamic Diameter (MMAD) is typically used to describe an aerosol in terms of the aerodynamic behavior of its particles, site(s) of particle deposition, and deposited mass. Particles in the size range of 1 to 10 µm deposit with relatively high efficiency in the upper respiratory tract and large airways, where inertial deposition is driven by high flow rates. Particles in the size range of 0.01 to 0.1 µm deposit by diffusion and are primarily taken up in the alveolar regions, where the large surface area enhances deposition by diffusion and sedimentation. The small airways do not have a single dominant mechanism of deposition.

Both empiric and mathematical approaches have been used to assess the dosimetry of inhaled particles. Direct measurements of deposition demonstrate that the human upper respiratory tract efficiently removes particles with an Mass Median Aerodynamic Diameter (MMAD) of approximately 5 µm. For particles in the 1- to 5-µm range, the total respiratory tract (upper respiratory tract plus conducting airways plus gas exchange region) deposition efficiency is on the order of 20%. Mathematically based estimates of the alveolar deposition efficiency of inhaled 1- and 5-µm aerosol particles are 5.2% and 17%, respectively.

Because of the nature of the mechanisms of deposition, deposited particles are not uniformly distributed on respiratory tract surfaces. Aerosols have been shown to deposit preferentially on the ridges of airway bifurcations, both in theoretical models and in direct observation of aerosol behavior using airways casts. Experimental observations of ciliary activity and mucous flow suggest that the concentration of particles on the ridges of airway bifurcations could, in part, result from trapping of particles on these ridges as they are cleared from more distal airways. Particles on airway ridges or branch points are cleared with a half-life of approximately 1 hour.

Particles deposited in the airways are rapidly cleared by the mucociliary escalator and by airway macrophages. Within 24 hours, most particles with a diameter of 1 µm are cleared from the airways. Particles initially deposited in the alveolar region are primarily cleared by macrophage phagocytosis. Clearance from the alveolar region is considerably slower than clearance from the airways, and removal of insoluble particles may require weeks to months.

Immunologic Responses

Immunologic responses can be classified as nonspecific or innate immune responses (actions of macrophages, monocytes, lymphocytes, and granulocytes) or agent-specific immune responses (immunologic memory of T and B cells). The innate defense mechanisms include a combination of phagocytosis and cytotoxic effects by effector cells and activation of the complement cascade. In the adaptive response, a large population of antigen-specific lymphocytes is produced that results in a potentially greater and prolonged immune system response. The adaptive response occurs when an antigen derived from the toxicant exposure is processed and presented by a dendritic cell, macrophage, or monocyte to a lymphocyte. The lymphocyte then undergoes clonal expansion to produce large numbers of cells that are specific for the particular toxic agent. Cytotoxic T-cell production occurs by this process when major histocompatibility (MHC) is expressed by the antigen-presenting cells in association with toxicant-derived antigen. Activated T cells produce numerous cytokines, such as tumor necrosis factor, that significantly enhances the immune response and the inflammatory responses of resident lung cells. Antibodies specific to the antigen are produced by B cells, which are stimulated by the interleukins to produce memory cells and plasma cells.

The effects of inhaled particles on human health are likely to involve inflammation, hypersensitization, and immunologic memory of T and B cells. These mechanisms are capable of amplifying injury initiated by repeated, low-dose exposures to antigens and therefore have the potential to produce significant effects at ambient levels of exposure. The pulmonary immune system differs from the systemic immune system in its ability to produce localized cell-mediated immune responses on repeated exposure to inhaled antigenic materials. Such localized response may play a significant role in hypersensitivity pneumonitis. Particles that contain metals have been shown to produce these responses. For instance, nickel and other transition metals are highly toxic and known to produce delayed hypersensitivity. Recent studies indicate that T-cell recognition of metal-complexed haptens plays a role in T-lymphocyte immune responses.

The airway epithelium and the alveolar epithelium are the primary lung surfaces on which inhaled toxicants may be initially distributed and/or react. The airway epithelium is a likely critical target site for an inhaled toxicant, as it is the first cellular barrier to inhaled toxicants and the most densely populated of the target surfaces. These aspects are offset to a large extent by the protection afforded by the thick mucous layer overlying airway epithelial cells and the efficient ciliary propulsion system. The alveolar epithelium of the gas exchange region has a large surface with a relatively low density of cells covered by a thin surface film. The thin surface film of the alveolar epithelial layer constitutes a critical site of possible action for pollutants not filtered by proximal airways. The outermost region of the respiratory path is the pleura, and this site is typically involved in toxic processes only after secondary transport following initial uptake of the reactive substance in more proximal air spaces. At each level, the presence or absence of adverse effects of inhaled particles and reactive gases is primarily determined by the unique immune response system in the lung.