1

THE MYSTERIOUS PINEAL ORGAN

2011 ROMESH SENEWIRATNE (MD)
In early 1995 I read, for the first time, that the famous French scientist and philosopher Rene Descartes had thought the pineal to be the seat of the soul, and that the ancient Indians had thought the organ to be the third eye for perceiving truth. This is, of course, common knowledge, but I had not learned these historical facts in medical school.

After six years as a medical student in Brisbane, followed by three years of post-graduate training (the last as a paediatric registrar) at the Royal Brisbane Hospital, when I embarked on a career as a general practitioner in 1986, all I knew about the pineal organ in the brain was its rough location and that it often calcifies progressively the older one gets. If such calcification is evident, seen as a white spot in the middle of the brain, the pineal, we learnt, can be used to detect midline shift on anterior-posterior X-ray views of the skull. Midline shift, we were taught, indicates a space occupying lesion on one side of the brain (such as a brain tumour or subdural haematoma).

In the pre-CT-scan days, when I trained to become one of thousands of Australian doctors, looking for midline shift of pineal calcification on skull X-rays was imprinted into our minds as an essential investigation for unexplained headaches or loss of consciousness. In one sense, an unconscious patient, or one with a suspected brain tumour, was lucky if he or she had a calcified pineal it meant mid-line shift could be picked up early, allowing early diagnosis and treatment. Such calcification as seen on plain X-rays of the skull, first described by Schuller in 1918, was

regarded as physiological meaning not pathological (indicative of disease).

Pineal calcification was recognized as sometimes being abnormal, and suggestive of pineal tumours. Radiologists were trained to report on calcification greater than 1cm in diameter (larger than the usual size of the pineal), since this could mean the gland was enlarged by a tumour, of which there are several types. Pineal calcification less than a centimeter in diameter was regarded as physiological, or normal, and therefore not worth reporting.

The question of whether or not so-called physiological calcification is actually normal, or whether it indicates loss of function of the pineal, only became relevant after the discovery at Yale University, by the dermatologist Aaron Lerner and co-researchers, of melatonin, the principle hormone secreted by what was then recognized, again, as a gland (the famous Roman physician Galen given it the name glandaris pinealis in the 4th century AD). This discovery of melatonin was in 1958 at Yale University, prior to which the pineal was generally regarded as vestigial, and to have no function in human beings.

The pineal organ has been the subject of one of the biggest, and least commented on, reversals of opinion in modern medicine and physiology. Up until 1958, when the hormone melatonin was isolated from cattle pineal glands by Dr Aaron Lerner, the pineal body, as it was called, was widely regarded as vestigial by the medical profession. The fact that the organ tends to calcify with age was taken as proof that it serves no function in humans. This claim is made explicitly in the 1957 edition of the reference text Histology by Arthur Ham, Professor of Anatomy at the

University of Toronto and Head of the Division of Biological Research at the Ontario Cancer Institute in Canada: The pineal body, also called the epiphysis, is a little coneshaped body about 1 cm. in length. Although it originates from, and remains connected to, the posterior end of the roof of the third ventricle, it projects backward so that it lies dorsal to the midbrain The pineal body of mammals is the vestige of the median eye which was probably a functioning organ in certain amphibia and reptiles that are now extinct. Like other vestigial organs in man, it tends to reach its greatest development relatively early in life and thereafter to degenerate. One evidence of the latter process is the formation of calcified bodies of a laminated appearance in the organ. These constitute what is called brain sand. (pp745-6, emphasis added)

Photomicrograph of pineal tissue in 1957 edition of Hams Histology

Though maintaining that the pineal is a vestige, Arthur Ham explains, in his 1957 text (a standard textbook in histology for medical students in Australia) that: The function of the pineal has been studied by the same means that have been employed for the study of endocrine glands. The effects of the removal of the pineal body from young animals have been investigated, as have the effects of grafting a series of pineal transplants into animals. Various types of extracts made from pineal bodies have been fed or injected into animals. The effects of pineal tumors on men and women have been noted. The net result of all this study is difficult to assess. The experimental results are conflicting. Nevertheless, there is some evidence to suggest that there is some association between the sexual development of the male and the pineal body. However, the nature and significance of this association are still obscure. (pp.746)

Aaron Lerner, who also discovered the pituitary hormone Melanocyte Stimulating Hormone (MSH), was looking for the pineal factor that had been observed, back in 1917, to cause lightening of frog skin. Though the dermatologists hope that the discovery might help understand, or treat, the de-pigmenting skin disease vitiligo remains unrealized, his discovery of the chemical structure of melatonin, in 1958, spawned a fascinating chain of research that has continued to the present day. This research, from many disciplines, has shown the pineal to influence the endocrine and immune systems, in particular. In addition to influencing the timing of pituitary hormone release (thus influencing our entire endocrine system), melatonin has been shown to be a potent anti-oxidant and scavenger of free radicals a property of the molecule with considerable relevance to the prevention of heart disease, stroke, dementia and cancer.

Importantly, the secretion of melatonin, which occurs at night, is suppressed by exposure to bright light, and synthesis of melatonin from the well known indole amine serotonin comes under control of the autonomic nervous system, mainly the sympathetic branch, though more recently parasympathetic innervation of the pineal has also been reported.

The sympathetic innervation of the pineal gland was first described by the Dutch neuroscientist Johannes Ariens Kappers in 1960. Kappers discovered that the primary innervation of the mammalian pineal comes, not from the brain, but from the superior cervical ganglia in the upper neck, the uppermost of the paravertebral sympathetic ganglia. Though the initial studies demonstrated this to be the case in rodents, subsequent studies showed the same to be the case in other mammals, including humans.

Between 1960 and 1980, during what some authors have described as the era of pinealology, numerous studies elucidated the mystery of what had previously been regarded as a vestigial organ, further. It was established that the sympathetic inputs to the pineal (from the superior cervical ganglia) came under the control of the suprachiasmatic nucleus (SCN), a structure the size of a grain of rice in the anterior hypothalamus. The SCN plays a central role in circadian rhythms, and has been described as a biological clock. It was established that the suprachiasmatic nuclei receive neural input from the eyes, and that changes in environmental lighting alter neural activity in the SCN, and consequently secretory activity in the pineal.

During these years, details of the synthesis of melatonin from the amino acid tryptophan via the increasingly well-known molecule serotonin were worked out, including the enzymes and co-factors involved in the

biochemical pathway. The fact that melatonin has an effect on the timing of pituitary hormone release (especially pituitary gonadotrophins) was established; this was shown to be the case in many mammals, including humans. Details of the mechanism by which the neurotransmitter noradrenaline (norepinephrine) in the sympathetic synapses stimulates synthesis of melatonin from serotonin were elucidated, and it was shown that synthesis of the enzyme NAT (Nacetyl-transferase), the rate limiting step in the synthesis of melatonin, was stimulated by noradrenaline and inhibited by exposure to light shone into the eyes. It was also reported that people who are totally blind (and rats that have their optic nerves severed or their eyeballs removed) lose the usual circadian rhythmicity of melatonin secretion.

The following diagram shows the metabolic pathway for the synthesis of melatonin from tryptophan. Serotonin is an intermediate molecule in this pathway, and this neurohormone/neurotransmitter is also known to be concentrated in the pineal. Conversion of serotonin to melatonin, which occurs at night (usually during sleep) is dependent on the catecholamine neurotransmitter noradrenaline (norepinephrine).

Fig.3

PINEAL CALCIFICATION: PHYSIOLOGICAL OR PATHOLOGICAL? Regarding so-called physiological pineal calcification, the first indication that this may not be normal came from startling reports from Uganda and Nigeria in the early 1970s. These studies showed that sub-Saharan Africans had much lower incidences of calcification, as seen on X-ray, than had been reported in the USA and Europe. A subsequent study in Cincinnati General Hospital, published in 1974, compared black and white Americans, and found that in populations living in a similar environment, the 300 blacks studied (9.8% of whom had visible pineal calcification) showed significantly less calcification than the 16% of 200 whites in whom a pineal opacity could be seen, though considerably more than that reported from populations in Nigeria (5 percent of 952 patients reported by Daramola and Oluwu in 1972) and Uganda (2 percent of 100 patients by Murphy in 1968).

Since pineal calcification increases with age, and appeared to vary between the sexes, the 1974 study by Adelola Adeloye (Rockefeller Fellow at the Childrens Hospital Research Foundation at the University of Cincinnati in Ohio) and Benjamin Felson (Professor of Radiology at the University of Cincinnati College of Medicine) compared different age groups of blacks and whites, as well as gender (comparing black and white populations remains a common feature of American medical science, although more recent papers and texts tend to include Hispanics as a third group for comparison).

Published in the November 1974 issue of the American Journal of Roentgenology, Adeloye and Felsons paper, titled Incidence of Normal Pineal Gland Calcification in Skull Roentgenograms of Black and White Americans, presented their findings in the following table:

As can be seen, most of the subjects in the study were children under the age of 19; only two of these showed pineal calcification, both black. In older age groups there was a greater tendency to calcification in whites, when the number of blacks (300) and whites (200) are taken into consideration, with a greater tendency towards calcification seen in white males and black females above the age of 20. The following table, from the same paper, shows the relevant percentages:

10

The fact that by the mid-1970s it had been conclusively shown that pineal calcification is not a ubiquitous phenomenon, affecting American Caucasians significantly more than African-Americans, and dramatically more than Indians, Polynesians and Africans, escaped the attention of doctors, like myself, who trained in Australia. The idea, then commonly expressed in the international literature, that pineal calcification may be abnormal or unhealthy was not suggested to us.

Studies since the 1960s indicate that the pineal, though certainly having a glandular function, also has other physiological activity almost certainly neuronal (electrical), and possibly magnetic; functions that may well justify the title of pineal organ, rather than merely a gland.

DISCOVERY OF THE PINEAL

The pineal was so named because of its shape the famous Roman physician Galen thought it resembled a pine cone. Galen, whose medical writings were unchallenged for more than a thousand years in the West, wrote that the ancient Greek physicians Herophilos and Erasistratos regarded the pineal gland, the glandaris pinealis, to be of special importance.

Partly based on its prominent midline location, the fact that it is an unpaired structure and the organs generous blood supply, the French philosopher and scientist Rene Descartes accorded equal respect to the pineal during the European renaissance.

Though the pineal has been known of since ancient times, and such luminaries of classical Greek and Roman science as Erasistratos,

11

Herophilos and Galen accorded importance to it, throughout most of the 20th century the pineal body was consistently described in medical texts as a useless vestigial remnant of our evolutionary ancestry from lower vertebrates. The calcification noted on post-mortem and frequently seen on X-ray was seen as further evidence that the pineal served no physiological function in humans, despite mounting evidence of its extraordinary range of activity in both cold and warm blooded vertebrates, ranging from fish, amphibians and reptiles to birds and mammals.

PHYSIOLOGY OF THE PINEAL ORGAN Evidence has mounted since the 1960s that the pineal acts as a neuroendocrine transducer an organ that converts electrical neural signals into hormonal (endocrine) signals. Specifically, release of the hormone melatonin (which occurs mainly at night and is suppressed by exposure to light) affects the timing of pituitary hormone release, thereby affecting the timing of widespread physiological events in the body. In addition, it has been conclusively proven that the main innervation of the pineal organ in mammals (including ourselves) comes from the sympathetic nervous system the so-called fight or flight branch of the autonomic nervous system.

The research data, and conclusions made by various pineal authorities are complex and sometimes contradictory. While volumes and careers, in the fields of anatomy, physiology, endocrinology, neuropsychiatry and neurology, have been devoted to study of the pineal organ, textbooks that might be expected to describe the known physiology and metabolism of the pineal and its secretions say nothing about the gland, especially in the late 1980s and 90s when drugs known to affect pineal function were widely (and wildly) prescribed. At the same time, other literature, ranging from science fiction to religious and parapsychology

12

writings, has had a lot to say about the pineal and its association with what was described as a Third Eye.

The association between the Eastern concept of the Third Eye and the pineal may have been a significant motivating force behind Western scientific skepticism towards discoveries by zoologists that the pineal organ does, in fact, function as a light-sensitive third eye in some living reptiles and amphibians (and not just in extinct ones as was thought up till the 1960s). Likewise, Descartes famous quote that the pineal is the seat of the soul may have acted as a disincentive for the modern scientific establishment abandoning the previously dominant vestigial theory. Talk of souls and spirits is generally viewed as the domain of priests, philosophers and psychiatric patients by the largely atheistic scientific and medical research industry.

Although Descartes has been ridiculed by later scientists for his claims about the pineal, he has, more often than not, been taken out of context and misunderstood. Russell Reiter, in his three-volume specialist text The Pineal Gland writes that Descartes stressed that the soul cannot be localised or confined to any single part of the body: Rene Descartes (1596 to 1650) or Cartesius is commonly cited as stating that the pineal gland is the seat of the soul. Often, modern scientists consider this statement quite incomprehensible and even ridiculous due to the general failure of forgetting that, in historical as well as modern times, most ideas and theories are influenced by the knowledge and philosophical background prevailing at the time in which they are conceived. This holds very strongly for the work of Descartes. At the end of the 16th and the beginning of the 17th century, the problem of the localization of the soul was very much discussed by both scientists and philosophers. Having a synthesising mind, Descartes gave expression to current ideas which were, however, mostly based

13

on ancient concepts. He reasoned systematically using rather ingenious mechanistic theories on the function of the brain, the sense organs, and the muscles which were based, mostly, on those of earlier authorsIn his Passions de lAme, Descartes emphatically says that the soul, his anima, cannot be localized exclusively to any precise part of the body because it is related to all body parts according to its very nature. This is, in fact, an old Aristotolean doctrine to which Augustinus (354 to 430) did agree, although Aristotle finally thought that the soul would be seated in the heart. (p.5)

Talk of third eyes and the seat of the soul are only two of many reasons that the pineal organ has been the subject of scientific, religious, political and financial intrigue, secrecy and suspicion, over recent decades. Another, very obvious, reason is the financial rewards of selling drugs in the case of the pineal, selling melatonin and SSRI drugs. Melatonin is currently being promoted as a nutritional supplement and for treatment of jet lag and insomnia, amongst many reasons plantderived melatonin is voluntarily ingested these days.

Pineal research is fundamentally related to serotonin research, serotonin being the neurotransmitter targeted by LSD, MDMA (Ecstasy) and SSRI drugs, of which Prozac (fluoxitine) was the first. The era of pinealology lasted from 1958, when melatonin was discovered, until the early 1980s, when it was replaced by the era of SSRI antidepressants and the Prozac generation. This generation had not been taught, and therefore could not remember, that only a few years earlier the pineal was thought to be as useless as the appendix.

14

THE FUNCTION OF THE PINEAL ORGAN IN HUMANS During the 1960s, much was discovered about the pineal organ in humans and other vertebrates. It was discovered that melatonin is synthesised from serotonin, and serotonin from the amino acid tryptophan. The chemical structures of these indole amines was discovered along with those of the enzymes involved in the synthesis of serotonin and melatonin. It was discovered that light shone into the eyes suppressed nocturnal melatonin production, and that the neurohormone affects secretion of other hormones, especially those secreted by the pituitary gland.

It was also found that the pineal functions as a third eye in certain reptiles and amphibians, and probably as a light-sensitive magnetosensory organ in birds. The function of the organ in various mammals remained controversial, however.

That pineal tumours can cause precocious puberty (abnormally early development of puberty) in humans was known as early as the 1890s, however only in the 1970s did it become evident as to why this occurs. Even now opinion is divided, but it is generally agreed that the secretion of melatonin (and other pineal hormones) affect the gonadotropins secreted by the pituitary gland (FSH and LH). These affect the endocrine activity of the testes and ovaries. Specifically, melatonin appears to inhibit the activity of luteinizing hormone (LH), the anterior pituitary hormone that regulates secretion of testosterone in male mammals and oestrogen in females. The full story of the pineals role as an endocrine organ is much more complex than this hormone secretion other than of the gonadotrophins is affected by the pineal and its main neurohormone, melatonin. Also, it is now thought that melatonin affects the activity of the immune system as well as the endocrine system. This

15

would not be surprising, since the two systems are closely related and many hormones have effects on multiple systems.

In the 1980 (ninth) edition of Harrisons Principles of Internal Medicine Professor Richard Wurtman (Professor of Endocrinology at the Massachusetts Institute of Technology) wrote that the pineal is now regarded as a neuroendocrine transducer: Since the discovery of melatonin in 1958, compelling evidence has accumulated that the mammalian pineal is not a vestige but an important component of a neuroendocrine control system. This organ has been shown to function as a neuroendocrine transducer. It receives a cyclic input of sympathetic nervous information which is suppressed when the retina responds to light. In response to this input, the pineal secretes a hormone, melatonin, into the bloodstream, much as the adrenal medulla releases epinephrine [adrenaline] in response to cholinergic nervous stimulation [using the neurotransmitter acetyl choline]. The synthesis and secretion of melatonin vary with a 24-h periodicity, thereby providing the body with a circulating clock apparatus. Until very recently, no assay was available to permit measurement of melatonin in human blood or urine. Largely as a consequence, human pineal physiology remained largely conjectural, and the only disease states that could clearly be associated with pineal malfunction were those caused by pineal neoplasms [tumours]. Now the melatonin in blood and urine can be measured by bioassay and radioimmunoassay, and it is apparent that the same factors that control the synthesis and secretion of this hormone in experimental animals also do so in humans. There is thus reason for optimism that our understanding of pineal physiology and pathophysiology, and of the possible medical use of pineal compounds, will soon expand. (p.1812) (emphasis added)

16

A few years after these words were written melatonin began to be marketed as a treatment for jet lag and was available for public consumption. It could be purchased in airports around the USA and was being marketed as a safe, natural tablet to reset the body clock. It was later marketed as a treatment for seasonal affective disorder (SAD, or winter blues), which was said to also respond to light therapy. Light therapy, as it was practiced, meant merely exposing the sufferer to artificial light (winter blues was claimed to be caused by chemical imbalances consequent on the shortening of daylight hours in winter). Meanwhile, drugs that affect serotonin, the indole amine that is converted to melatonin in the pineal, were launched with much fanfare and publicity, spearheaded by Eli Lilly, the manufacturers of the first of the selective serotonin re-uptake inhibiting (SSRI) drugs, Prozac (fluoxetine).

THE PINEAL AND PSYCHIATRY The relationship between the pineal and the psychiatry profession is discussed by Professor Josephine Arendt in Melatonin and the Mammalian Pineal Gland in a section titled melatonin in psychiatric disorder. She wrote, in 1995: Abnormalities in circadian function have been postulated in depression and mania. Melatonin is arguably the best index of biological clock function: only bright light masks the expression of the endogenous rhythm, and it has been extensively used in psychiatry and in other fields to assess biological clock status. There is evidence for a decline in amplitude of the melatonin rhythm in depression and in schizophrenia. In depression this is associated with an increase in cortisol. There is possibly an

17

increase in amplitude in mania although not all studies are consistent. There is little evidence for abnormal timing of melatonin, although Lewy (Lewy et al., 1987) has reported exceptionally delayed melatonin rhythms in winter in patients with seasonal affective disorder (SAD) compared to the small delay seen in normals. This observation remains to be confirmed but is of considerable theoretical interest. The treatment proposed for SAD patients was the creation of an artificial summer day length using 3 hours of bright full spectrum light (Vitalite, 2500 lux) morning and evening. The melatonin hypothesis predicted that such light treatment would shorten the duration of melatonin secretion thus generating a summer day length signal by analogy with animal work. The light treatment appears to be efficient but it does not appear to work through melatonin. Bipolar (manic depressive) patients are more sensitive to light suppression of melatonin than normals. This observation may prove to be of both diagnostic and therapeutic importance. Most pharmacological antidepressant treatments will stimulate melatonin secretion through increased availability of the precursors tryptophan and serotonin and the major pineal neurotransmitter noradrenalin, or by direct action on serotonin and catecholamine receptors. There may be a link between an increase in melatonin production and efficacy of treatment and this possibility merits exploration. (p.237)

Professor Arendt and her co-workers at the University of Surrey in the UK have tested melatonin levels in many psychiatric patients including people diagnosed with anorexia nervosa, manic depression, depression, schizophrenia and mania. Although in the introduction of her book she says that pineal research is truly interdisciplinary and its participants are required to keep their perspectives broad while still remaining

18

absolutely rigorous, in terms of the mind sciences she looks no further than the latest psychiatric labels from the British and American psychiatric professions. Seasonal Affective Disorder, conveniently abbreviated to SAD is a new label for an old phenomenon (that may be worsening in negativistic societies) many people feel sad during winter, at least, sadder than they do in spring, summer and autumn.

Looked at more holistically, there are many reasons as to why people may feel unhappy, tired, and bored in winter (in temperate regions) other than shortened day length, and many social and environmental consequences that accompany shortened day length which can contribute to depression (a broad term which can include sadness, boredom, anxiety and anger). The obvious reason is that it is cold and tends to rain more. People tend to stay inside more, and the overall level of social isolation in society tends to increase. Many people feel socially isolated anyway, and feel better with even minimal attention from others (because they get so little). This may explain why the Vitalite, 2500 lux works to alleviate SAD. People who are sad and isolated may be particularly prone to placebo effects and suggestions that treatments will be efficacious. Sitting in bright light may well be safer and more effective than taking Prozac or Prothiaden (a commonly prescribed tricyclic antidepressant). Both these drugs, along with others of their class, evidently affect pineal function and the secretion of melatonin together with their better known effects on serotonin and noradrenaline. It is also clear that the long-term risks of interfering with pineal activity are presently unknown, as are the full functions of the organ although this has not stopped several researchers, including Professor Arendt herself, experimenting on themselves by taking timed melatonin since as far back as 1981. In the acknowledgements of her 1995 book she wrote: Vincent Marks gave essential help and encouragement both to establish my laboratory in the UK and to fund our work. John

19

Wright enables our clinical studies in many ways not least by his ability to stay awake all night while taking blood samples. He and I first took timed melatonin in 1981 and realized its potential.

The list of sponsors for her research gives some indication of those with a particular interest in knowing about melatonins role in humans: Our work has primarily been funded by the Swiss National Science Foundation, the MRC [British Medical Research Council], the AFRC, the Wellcome Trust, the British Antarctic Survey, the South West Thames Regional Health Authority, the Ministry of Defence, several pharmaceutical companies and our own company Stockgrand Ltd.

Professor Arendt promotes the therapeutic benefits of melatonin enthusiastically in the foreword of Melatonin and the Mammalian Pineal Gland (although she does present some concerns at the end of the book): At present it could almost be considered the best candidate for a universal panacea. It has been proposed as the treatment of choice for an enormous range of ills, the most reasonable being natural rhythm disturbance occurring when our biology conflicts with our culture such as shift work and jet lag, and the unnatural lighting conditions, especially in winter, in which we live. It has essentially founded a whole new pharmacology which is yet in its early infancy. (p.4)

On page 282 Professor Arendt summarises what she regards as problems with the therapeutic use of melatonin: 1. Its effects are time and dose dependent.

20

2. The effects may be stimulatory, inhibitory, or ineffective depending on current and previous photoperiodic experience, circadian status, developmental stage, and previous exposure. 3. There may be long-term consequences of treatment which are beneficial. On the other hand they may also be detrimental. 4. There are no published full toxicity studies. 5. There may be undesirable effects on cardiovascular function including clotting. [a potentially disastrous risk] 6. Intermittent reported undesirable side effects include headache and nausea. 7. Its interactions with other drug treatments are unknown.

These are all significant reasons to exercise caution in taking melatonin, and there are others. The fact that there are no published full toxicity studies illustrates that what is published tends to favour the use of drugs rather than discourage it. At the same time propaganda prematurely proclaiming the effectiveness of new drugs has now been expanded through the mass media we are increasingly subjected to various drug promotional strategies on the Internet and when we watch television, listen to the radio or visit our local library. It was on a visit to my local library in 1997 that I discovered, for the first time, how deeply the psychiatric profession has been involved in pineal research and melatonin promotion.

The book that drew my attention to this was written by an American psychiatrist, Micheal Norden, and published by Harper Collins in 1996. It is called Beyond Prozac and claims, on the back cover, to be a provocative and enduring classic in the modern literature about mental health. The promotional blurb on the back cover boasts:

21

In Beyond Prozac, Dr. Michael Norden, a psychiatrist and pioneer in developing new applications of Prozac, explains how the toll of modern-day life has undermined our health and led to a national epidemic of depression, anxiety, and weight problems. But there is hope. Based on seven years of groundbreaking research and clinical work, Beyond Prozac offers solutions to these chronic health problems that go beyond simply prescribing Prozac from incredibly effective alternative treatments such as light therapy, regulation of sleeping habits, and specialized diets to the next generation of safer and more effective depression medications. A decisive voice in the debate about depression, Beyond Prozac is a provocative and enduring classic in the modern literature about mental health.

Dr Norden does not write about mental health he writes about new drugs for the treatment of depression the name of his book says it all. Although a psychiatrist by profession, he does not write much about the mind he writes, instead, about behavior and chemicals, repeatedly making the familiar claim of chemical imbalances as being at the root of mental illness. In addition to promoting the new SSRI antidepressants, Dr Norden also promotes St Johns Wort (hypericum, a European herb which is now being marketed in capsule or tablet form), light therapy units (which he says can be bought for less than $200) and melatonin supplements. The latter he recommends to boost the immune system and as an anti-ageing hormone, and for the treatment of sleep disorders, stress and depression, admitting that he had conducted trials on his own patients: I recently began using melatonin on a limited basis in my practice. Some patients reported excellent improvement in their sleep. More exciting, some found that melatonin also reduced their stress and improved their mood. These anecdotal observations certainly made me eager to see further investigation

22

of melatonin therapy for a range of stress-related conditions. (p.53)

Stress-related conditions, ageing people (who are concerned about their ageing) and people who want to boost their immunity provide a growing market for melatonin marketers in the USA and around the world. Not as many people are shift workers and even fewer suffer from jet lag. As far as risks are concerned, Dr Norden urges less caution (and caution for different reasons) than Professor Arendt: Apparently millions of Americans are already taking melatonin. This amounts to a massive uncontrolled experiment, not unlike many aspects of our modern living. People need to know that there is a risk involved in this experiment. One aspect of the risk involves the lack of control regarding the strength and purity of the melatonin supplements. Under no circumstances would I suggest anyone take melatonin derived from animal sources; you never know what might show up in such a preparation. This is one time when clearly natural sources are inferior you want synthesized melatonin. Fortunately, most all the melatonin now available appears to be synthesized. Attempt to obtain pharmaceutical-grade melatonin and choose the most established manufacturers, as they have the most to lose from any lapse in quality control. Watch for reports of independent testing of preparations. Melatonin itself appears to be one of the most benign substances known. There is no indication that any amount is lethal, which cannot even be said for water, let alone oxygen which is quite toxic in high doses. However, it is known that high doses of melatonin will suppress gonadal function in animals. Most users, therefore, should try only low physiological doses. Testicular atrophy is presumably not one of the aspects of enhanced sexuality claimed by ardent proponentsSome companies now

23

claim sustained release action for their preparations, which in theory should be a more natural way to deliver melatonin, simulating the bodys continued release through the night. (p. 60)

The most obvious concern about taking melatonin is dismissed without discussion, or clarification as to whether this problem has been looked for: One particular concern is the possibility that taking melatonin may suppress the bodys own production of melatonin, though there is no evidence that this occurs. (p. 60)

Surprisingly, Professor Arendt does not address this concern (or mention it) in her list of problems with the therapeutic use of melatonin. She agrees with Dr Norden that melatonin can be used in clinical trials with safety and has very low toxicity (p.250) and is reassured by the results of early trials with enormous doses of melatonin: Enormous doses of melatonin (50 mg to 6.6 g = 33 million pineals!) in the daytime had no beneficial effects on Parkinson patients, Huntingtons chorea, depression (in fact depression was worsened) and schizophrenia. Skin pigmentation was not affected: human pigment cells do not resemble amphibian melanophores in pigment migration phenomena. Small decreases in plasma LH and FSH were observed. Large amounts of melatonin such as these may produce headache and abdominal cramps. This may possibly be due to a false transmitter effect on serotoninergic systems. (p.251)

One wonders if the Parkinson patients knew that they were being given the equivalent of 33 million pineals in a single dose one which stimulates an exclamation mark in the otherwise dry and unemotional

24

text of Melatonin and the Mammalian Pineal Gland. It is evident that once human trials with melatonin began in earnest in the 1980s, psychiatric patients, as in the case of insulin in the 1920s and oestrogen in the 1930s, provided a convenient captive population on which to experiment. While there is no doubt that Professor Arendt knows a great deal about the pineal and melatonin, it is evident from her many references to psychiatric labels that she has not considered deeply or critically the social and political history of psychiatry, nor its contemporary theory and practice. She routinely refers to melatonin levels in various categories of patient (Parkinson, schizophrenic etc.) comparing them with normals. One gets the impression that she spends more time analysing labelled blood tubes and urine specimens than listening to labelled human beings. In fact, she provides an argument for using melatonin levels to biochemically label people as manic depressive.

Earlier, in the preface to Melatonin and the Mammalian Pineal Gland, Professor Arendt makes a surprising admission, and a profound endorsement of the importance of tolerance, love and understanding: The small Channel Island of Guernsey, where most of this was written, restores my sanity at frequent intervals. Finally I have to say that without the tolerance, understanding and love of my husband and family I would not have been able even to contemplate this book. I hope they feel that their domestic and other supportive efforts have allowed me to produce something worthwhile.

The surprising admission is that the small Channel Island of Guernsey restores the professors sanity at frequent intervals. What sort of insanity does she suffer from when she stays in Surrey for too long?

25

OMISSION OF INFORMATION ABOUT THE PINEAL If you ask a medical doctor what the pineal organ is and does, you will, more likely than not, be told it is a small gland in the brain about which little is known. You might be told that it secretes a substance called melatonin, and that this is produced mainly at night. If the doctor is wellinformed, you might be told that the organ also secretes other substances, that melatonin is made in the pineal from the well-known indole amine, serotonin, and that the pineal was thought, by the French scientist Descartes, to be the seat of the soul back in the 1600s.

These facts are all true, but there is much more to the story of the pineal and a much more profound mystery associated with the pineal than the important scientific question of what melatonin does. The biggest mystery about the pineal is why most doctors do not know even rudimentary facts about an important organ in the brain, and why these facts are omitted from student texts and post-graduate medical texts about the brain but not from the medical literature altogether. Why it is mysterious is that no other part of the brain has been subject to the same degree of omission. Neurosciences textbooks contain much detail about the pituitary gland, and the hypothalamus, other important parts of our endocrine system; however the same books often fail to mention the pineal. They not only fail to mention the fact that it secretes serotonin and melatonin, but sometimes ignore the organs existence completely (see Kandel, 1995; Kotulak, 1996; Kolb & Whishaw, 1990). This is despite more and more evidence of the organs importance in human and in other mammals.

Since I noticed this anomaly, in 1995, I have considered several theories about what has caused it. The first was that little is known about the pineal, and because what has been discovered is uncertain, it is not presented in textbooks. This theory was refuted by the observation that

26

important recent discoveries about the pineal were included in the 1980 edition of the reference medical text Harrisons Principles of Internal Medicine (published by McGraw Hill) but excluded from later editions of the same textbook. These discoveries include the fact that the pineal is a complex organ with an intricate blood supply and a nerve connection to the visual system and the autonomic nervous system. This allows the glandular cells in the organ to modulate the amount of melatonin and other hormones it releases into the bloodstream according to physiological needs. The 1980 edition of the textbook describes this function of the organ as that of a neuro-endocrine transducer, meaning that it provides an interface between the brain and endocrine system. As such, it is obviously of central importance in understanding the brain-body relationship and the mind-body relationship. But that is not the only vital fact about the pineal that modern doctors are being deprived of by those who decide what is published in textbooks. This removal of information about the pineal, which occurred in the late 1980s, affected a range of textbooks published by major corporate publication companies based in the US and UK, including McGraw Hill, Churchill Livingstone and Appleton & Lange. A particularly outrageous example is the respected specialist textbook Essentials of Neural Science and Behavior published by Appleton and Lange, a subsidiary of Prentice Hall International. The international edition of this book, which is on sale in the bookshops of major universities in Australia, completely omits the pineal organ in their 1995 edition, and the same phenomenon can be observed in several other highly respected medical textbooks. Although most parts of the brain are discussed in detail in these books, the pineal organ is conspicuously absent.

Corresponding with this removal of physiological information about the pineal, serotonin has been associated with an extraordinary range of psychiatric abnormalities. The Universal Press publication Inside the Brain by Pulitzer prize-winning author Ronald Kotulak makes the following claim in his book, published in 1996:

27

Low serotonin is common to many problems in which one or more of our drives bursts out of its chemical corral. Medical researchers found that most of these disorders may be treatable with drugs that change serotonin levels. First developed to halt the uncontrollable aggression of schizophrenia and depression, these drugs are now being used or tested for a wide variety of problems, including alcoholism, eating disorders, premenstrual syndrome, migraines, anger attacks, manic-depressive disorder, obsessive-depressive disorders, anxiety, sleep disorders, memory impairment, drug abuse, sexual perversions, irritability, Parkinsons disease, Alzheimers, depersonalization disorder, borderline personality, autism and brain injuries. (p.88)

The pineal is not mentioned in this book, nor melatonin, let alone the concentration of serotonin in the pineal and the conversion of serotonin to melatonin. A similar phenomenon can be observed in the Time magazine article of September 1997 titled The mood molecule by Michael Lemonick. In this article serotonin is discussed in depth, however the pineal and melatonin are not mentioned, and the discussion is centred on drugs which affect serotonin, and, to a lesser degree, other neurotransmitters.

The 1980 edition of Harrisons Principles of Internal Medicine contained a clue as to why information about the anatomy and physiology of the gland may be so conspicuously absent from recent medical and neurological texts: There isreason for optimism that our understanding of pineal physiology and pathophysiology, and of the possible medical use of pineal compounds, will soon expand. (p.1812)

28

Melatonin began to be marketed in the early 1990s as a treatment for jet-lag, insomnia, aging, cancer and seasonal affective disorder with scant regard for the long-term safety of ingesting the hormone. SSRI antidepressants, which selectively affect serotonin, the indole amine from which melatonin is synthesised, and which is concentrated in the pineal (although it is also active as a neurotransmitter in other parts of the brain) were launched, beginning with Prozac, in the late 1980s and with similar nonchalance about long-term and short-term dangers.

The sympathetic innervation of the glandular cells in the pineal is adrenergic that is, it involves the catecholamine neurotransmitter noradrenaline. This was discovered by the Dutch neuroscientist J. Ariens Kappers. Back in the 1960s, noradrenaline was shown to be involved in the conversion of serotonin to melatonin, which occurs mainly at night and is suppressed by light entering the eyes. The influence of environmental lighting conditions on pineal activity shows that the connection between the visual system and the pineal, well documented in fish, reptiles and birds, is retained in mammals, including humans, although in mammals most of the fibres from the visual system make a circuitous connection from the suprachiasmatic nucleus of the hypothalamus (above the optic chiasma) to the superior cervical ganglia (in the upper neck). Nerve cells in the superior cervical ganglia send ascending sympathetic fibres to the pineal.

The suprachiasmatic nucleus, which has been described as our biological clock is known to be involved in the regulation of circadian rhythms in various mammals, and is also involved in diurnal and other physiological rhythms (Reiter, 1981; Arendt, 1995).

29

The 1980 edition of Harrisons Principles of Internal Medicine mentions Kappers discovery but not the evidence that suggested the pineal also has other nerve (neuronal) inputs: In 1960, Kappers made the important discovery that the primary innervation of the mammalian pineal originates not within the brain but rather from sympathetic cell bodies in the superior cervical ganglia. Subsequent studies using the electron microscope revealed that the sympathetic nerve endings terminate directly on pineal parenchymal cells in an anatomic relationship that resembles the synapse. The sympathetic innervation of pineal glandular cells appears to be a new evolutionary adaptation, which by itself invalidates the vestige theory of pineal function. (p.1812, emphasis added)

The American physician Richard Relkin (Professor of medicine at the Hahnemann Medical College in Pennsylvania), in his 1983 endocrinology text The Pineal Gland explained that, although the most obvious nerve tract (the nervus conarii) entering the pineal is connected with the sympathetic ganglia in the upper cervical (neck) region, the gland also has nerve fibres which enter the organ directly from the brain. These enter via the stalk of the pineal and have been largely ignored by researchers, who maintained for many years that they are aberrant fibres (and thus of no significance). These fibres (most of which appear to enter, rather than emanate from the pineal) are connected with many parts of the brain, notably with the thalamus and the auditory and visual systems. Professor Josephine Arendt wrote, more recently, in Melatonin and the Mammalian Pineal Gland (1995) that: there is reason to believe that multiple nervous inputs from peripheral sympathetic innervation and direct central [from the brain] innervation influence pineal function. The transmitters concerned with direct innervation may include a number of peptides such as vasoactive intestinal peptide (VIP), peptide

30

histidine isoleucine (PHI), arginine vasopressin (AVP), arginine vasotocin (AVT), oxytocinand luteinizing hormone releasing hormone. Initially, it was thought that central neural projections to the pineal formed hairpin loops in the pineal stalkand thus did not innervate the pineal. The loops certainly exist, but there is now substantial evidence for central innervation as described above. (p.15, emphasis added)

Earlier, Professor Arendt refers to studies demonstrating direct inputs to the pineal from the hypothalamus (including, but not only, from the suprachiasmatic nucleus). In addition to this central innervation the pineal is also innervated, she writes, by the pineal nerve, which carries both efferent [outgoing from the brain] and afferent [incoming to the brain] fibres, and whose function is presently unexplained: In the human, sheep and rabbit a pineal nerve is present, deriving from the subcommissural organ, with indications of both afferent and efferent fibres. This nerve has no known function at present but may be incorporated into the pineal stalk as part of adult central innervation. (p. 16, emphasis added)

The peptide oxytocin, mentioned by Professor Arendt as one of the transmitters involved in the pineal, is known to be secreted by the posterior lobe of the pituitary, after being synthesised in the hypothalamus. Known for many years to be involved in contraction of the uterus during labour, the hormone has recently been associated with feelings of affection and love. Luteinising hormone releasing hormone (LHRH), also thought to be active as a transmitter in the pineal, is so named because of its wellknown effect on the anterior lobe of the pituitary, where it stimulates the release of luteinising hormone (LH). LHRH release is thought to be

31

regulated by noradrenaline and dopamine in the hypothalamus. LH, secreted into the blood stream by the pituitary, travels all over the body, but its main known action is on the gonads, where it stimulates testosterone production and release in men and oestrogen production and release in women. Oestrogen (which is mainly produced by the ovaries) and testosterone (mainly secreted by the testes), like all the other steroid hormones (including cortisol) are manufactured from cholesterol. LHRH also regulates release of the other anterior pituitary gonadotropin, Follicle Stimulating Hormone (FSH), which stimulates the development of the ovarian follicle during the female reproductive cycle in mammals and spermatogenesis in males (Arendt, 1995).

The sections in Snells Clinical Neuroanatomy (1980) on the hypophyseal portal system and functions of the hypothalamus contains a useful summary of the integrated function of the hypothalamus and pituitary (hypophysis): The hypophyseal portal system is formed on each side from the superior hypophyseal artery, which is a branch of the internal carotid arteryThe portal system carries releasing hormones and release-inhibiting hormones, which are produced in the neurons of the hypothalamus, to the secretory cells of the anterior lobe of the hypophysis [pituitary]. The releasing hormones stimulate the production and release of adrenocorticotropic hormone (ACTH), follicle-stimulating hormone (FSH), luteinizing hormone (LH), thyrotropic hormone or thyroid-stimulating hormone (TSH), and somatotropic or growth hormone (STH). The release of inhibiting hormones inhibits the release of the melanocyte stimulating hormone (MSH) and luteotropic hormone (LTH). LTH (also known as prolactin) stimulates the corpus luteum to secrete progesterone and the mammary gland to produce milk. (p.403)

32

The importance of the hypothalamus to control of the endocrine system, is equalled by its importance to the autonomic nervous system, as Professor Snell continues in Clinical Neuroanatomy (1980): The hypothalamus has a controlling influence on the autonomic nervous system and appears to integrate the autonomic and neuroendocrine systems, thus preserving body homeostasis. Essentially, the hypothalamus should be regarded as a higher nervous center for the control of lower autonomic centers in the brain-stem and spinal cord. Electrical stimulation of the hypothalamus in animal experiments shows that the anterior hypothalamic area and the preoptic area influence parasympathetic responses; these include lowering the blood pressure, slowing the heart rate, contraction of the bladder, increased motility of the gastrointestinal tract, increased acidity of the gastric juice, salivation, and pupillary constriction. Stimulation of the posterior and lateral nuclei causes sympathetic responses, which include: elevation of blood pressure, acceleration of the heart rate, cessation of peristalsis in the gastrointestinal tract, pupillary dilation, and hyperglycemia. (p.404, emphasis added)

The text also mentions evidence of the involvement of the hypothalamus in temperature regulation and regulation of food and water intake, again based on experimental stimulation (with electrodes): Stimulation of the lateral region of the hypothalamus initiates eating and increases food intake. This lateral region sometimes is referred to as the hunger center. Stimulation of the medial region of the hypothalamus inhibits eating and reduces food intake. This area is referred to as the satiety center.

33

Experimental stimulation of other areas in the lateral region of the hypothalamus causes an immediate increase in water intake; this area is referred to as the thirst center. In addition, the hypothalamus exerts a careful control on the osmolarity [concentration of salts] in the blood through the secretion of vasopressin by the posterior lobe of the hypophysis [pituitary] and its influence on the distal convoluted tubules of the kidneys. (p.405)

Finally, Professor Snell mentions control of circadian rhythms as another function of the hypothalamus, omitting the pineal from his neuroanatomical perspective on circadian (24 hour) rhythms, temperature regulation and sympathetic innervation: The hypothalamus controls many circadian rhythms, including body temperature, adrenocortical activity, eosinophil count [a type of white blood cell], and renal secretion. Sleeping and wakefulness, although dependent on the activities of the thalamus, the limbic system, and the reticular activating system, are also controlled by the hypothalamus. Lesions of the anterior part of the hypothalamus seriously interfere with the rhythm of sleeping and waking. (p.405)

The pineal is, nevertheless, discussed in the 1980 edition of Clinical Neuroanatomy (unlike several contemporary neurosciences texts): The pineal gland or body is a small, conical structure that is attached by the pineal stalk to the diencephalon. It projects backward so that it lies posterior to the midbrain. The base of the pineal stalk possesses a recess that is continuous with the cavity of the third ventricle. The superior part of the base of the stalk contains the habenular commissure; the inferior part of the base of the stalk contains the posterior commissure.

34

On microscopic section, the pineal gland is seen to be incompletely divided into lobules by connective tissue septa that extend into the substance of the gland from the capsule. Two types of cells are found in the gland, the pinealocytes and the glial cells. Concretions of calcified material called brain sand progressively accumulate within the pineal gland with age. The pineal gland possesses no nerve cells, but adrenergic sympathetic fibers derived from the superior cervical sympathetic ganglia enter the gland and run in association with the blood vessels and the pinealocytes. The functions of the pineal gland are not fully understood. Melatonin and serotonin are present in high concentration within the gland. The noradrenalin from the sympathetic fibers probably stimulates the release of these substances from the pinealocytes. It is not known whether these substances leave the pineal through the capillaries or through the pineal recess into the cerebrospinal fluid of the third ventricle. There is increasing evidence that the pineal gland influences the output of gonadotrophins through the hypothalamus. Whether melatonin or serotonin is involved in this activity is unknown. (p226-7)

THE PINEAL AND SEXUAL FUNCTION The influence of melatonin from the pineal on pituitary hormone secretion in mammals was discovered during an intense period of pineal experimentation (using various animals) in the 1960s and 70s, and provides an explanation for the earlier clinical finding that pineal tumours can produce precocious puberty, reported in 1898 by the German physician Otto Huebner. This earlier finding, which should have prevented the misconception, prevalent in the 1950s, that the pineal is

35

vestigial, is mentioned by Professor Kappers in the introductory chapter of the first of a 1981 three volume series edited by Russel Reiter, Professor of Anatomy at the University of Texas, and, like the Dutch Professor Kappers, an international authority on the pineal. In Volume 1: Anatomy and Biochemistry in The Pineal Gland Kappers writes: In 1898, Huebner was the first to describe a boy showing signs of premature puberty and suffering from a pinealoma. At the end of the first decade of the 20th century, Marburg coined the term pubertas praecox or genitosomia praecox for the clinical syndrome which is characterized by premature development of the primary and secondary sex organs and a pineal tumourAccording to Marburg, the human pineal gland is an endocrine organ which, in infancy, would normally inhibit the function of the hypothalamus and thus, the development of the reproductive systemIt is not surprising that, in those days, the pineal gland was termed Keuschheitsdruse or chastity gland by some German authors. In the 1920s, Berblinger also attributed an inhibitory activity on gonadal development to the pineal, while Engel surmised from some experiments that pineal extracts would contain an antigonadotrophic hormone. Such extracts, like glanepin, were even used in clinical treatment. (p.9)

From Professor Ariens Kappers account it is evident that pineal extracts (made from crushed animal pineals) were being used as a medicine in Germany several decades before melatonin was discovered because of its speculated role in suppressing fertility. The theory on which this treatment was based assumed, correctly, that because destruction of the pineal (such as had been described by Heubner) caused premature puberty, pineal extracts might contain an antigonadotrophic (antifertility) hormone.

36

During the era of pinealology which followed the discovery of melatonin by Aaron Lerner in 1958 it was established beyond reasonable doubt that the hypothesised mammalian antigonadotropic hormone was, in fact, melatonin at least in rats. Kappers explains: the antigonadotrophic effect of melatonin seemed wellestablished, at least in rats, by a number of experimental investigations of which only a few will be mentioned here. Daily administration of melatonin to maturing female rats appeared, for instance, to cause retardation of the normal increase in ovarian weight, delay of normal vaginal opening time, and decrease in incidence of estrus, while the high incidence of estrus following pinealectomy could be blocked, at least statistically, by melatonin administration. Injections of melatonin administered to adult male rats resulted in a very conspicuous decrease in size of the seminal vesicles. (p.15)

Professor Josephine Arendt, in Melatonin and the Mammalian Pineal Gland (1995) describes these observations of the 1960s, and says that they were further clarified by the discovery that melatonin inhibited luteinizing hormone release from cultured pituitary gland cells in vitro, and delayed pubertal development in male and female rats (Arendt, 1995, p.274). She also suggests that, these results partially support the contention that in large doses, suitably administered, melatonin can inhibit human reproductive activity. The repeated and consistent finding that exogenous melatonin adversely affects reproductive function in rats and other mammals suggests that similar effects might be expected (and predicted) in humans who take melatonin tablets or drugs that influence the metabolism of the indole amines (notably SSRI antidepressants, clozapine, MDMA and tricyclic antidepressants). More recent evidence that the pineal is also involved in maintaining health of the immune system raises further questions about the safety of these drugs.

37

That melatonin from the pineal has an antigonadotropic effect is not in dispute, nor that this includes effects by the pineal on the pituitary release of luteinising hormone. Professor Mac Hadley of the University of Arizona, in the specialist textbook Endocrinology (1984), wrote, in the chapter on the endocrine role of the pineal gland: There is evidence for brain, pituitary and peripheral antigonadotropic actions of melatonin. The evidence for a CNS [central nervous system] effect is derived from the following information. Pinealectomy [surgical removal of the pineal] leads to increased motor and EEG activity, whereas melatonin administration reduces spontaneous motor activity, promotes sleep with slow EEG activity, and prolongs the duration of barbiturate induced sleep. Melatonin may modify CNS neurotransmitter function as increased levels of gamma aminobutyric acid (GABA) and serotonin have been noted in the brain after melatonin administration. Melatonin implants into the medial preoptic and suprachiasmatic and retrochiasmatic areas of the mouse brain mediates its hypothalamic effect by inhibition of gonadotrophin-releasing hormone (GnRH) synthesis and secretion. (p.476)

This 1984 text, another Prentice-Hall medical publication, continues with more reasons why the ingestion of melatonin and drugs that affect indoleamines might be expected to interfere with sexual function and other oestrogen and testosterone-dependent (or modulated) physiological activities (and hormonal balance, more widely): There is also evidence that exogenous melatonin decreases testicular androgen synthesis and that the indoleamine is inhibitory to the growth response of the rat ventral prostate gland to exogenous testosterone. Melatonin also decreases the weight of both the testes and the ventral prostate gland of

38

hypophysectomised [pituitary-excised] rats receiving testosterone. Pinealectomy enhances the growth response of the seminal vesicles to testosterone in castrated rats and administration of the indoleamine prevents the response to the androgen. These results suggest that the inhibitory influence of systematically administrated melatonin on the accessory sex organs may be due to its antagonistic effect at the level of the gonads. Melatonin excretion in normal males and females increases at puberty, and melatonin may play a role in adrenarche (pubertal changes induced by adrenal androgens) by an action on adrenal steroidogenesis. (p.476)

In 1997 it was reported in the Lancet that the age when children reach puberty is falling in the USA, following a study at the Kansas Childrens Hospital that found 6.7% of Caucasian girls and 27.2% of AfricanAmerican girls had breast development or pubic hair by the age of seven. Although it has been known since the 1890s that pineal destruction can cause precocious puberty, and the known involvement of the pineal (and melatonin) in the hypothalamo-pituitary-gonadal axis, pineal dysfunction was not suspected as being involved in this phenomenon. Could it be?

It is known that exogenous (from outside) administration of melatonin suppresses gonadal (sexual organ) activity this is thought to occur due to suppression of pituitary gonadotrophins (Luteinizing Hormone, in particular) and direct effects on the gonads (ovaries and testes). This suggests that endogenous melatonin has physiological effects on the gonads and sexual/reproductive function. The effects of pinealectomies in animals and pineal tumours in humans have further supported this theory but also indicated that, like the other amines, natural melatonin has many other physiological effects. These include effects on other pituitary hormones, on other parts of the brain and on cells throughout

39

the body. The latter are of particular importance to an understanding of the mind-body relationship and the brain-body relationship. They also provide further reasons for caution in the ingestion of melatonin or drugs that affect the incompletely understood, but undoubtedly vital, indoleamine and catecholamine pathways.

While there is irrefutable evidence that environmental lighting conditions affect pineal hormone synthesis and secretion (especially that of melatonin), it has been generally assumed that the visual information that enters the pineal via nerve fibres is concerned only with quantity (intensity and duration) rather than quality (light and visual experience in all its complexity). The neural connections of the pineal, including the intensively studied sympathetic connections and the less well-known direct connections (with the midbrain and diencephalon) allow for much more profound and subtle effects than the commonly cited fact that light entering the eyes suppresses nocturnal melatonin secretion. The diagram below presents an overview of the connections between the visual system and the pineal:
Fig. 4

40

Children in the Western World are, as a whole, undoubtedly subjected to more sexually explicit material, and more sexually-directed messages than was the case 40 years ago mainly as a consequence of television and the mass-media (and the advertising motto that sex sells). The neural mechanism by which precocious sexual development could result from pre-pubertal sexually-oriented audio-visual experiences (television programs, in particular) can be hypothesised in terms of known pineal neural and endocrine connections, particularly the organ/glands connection with the visual system. Such a hypothesis cannot be proved or disproved unless considered. This is the case also for the theory that watching television at night may interfere with natural melatonin rhythms, thus contributing to depression, and the theory that watching violent television programs increases violence in society. Of course, no theory can be proved or disproved until it is considered.

THE PINEAL AND THE IMMUNE SYSTEM

The connection between depression, the pineal and the immune system is interesting. It is generally accepted that psychological depression can cause immune depression an observation famously made by the Athenian general Thucydides 2500 years ago when describing the effects of a diagnosis of plague: The most terrible thing of all was the despair into which people fell when they realised that they had caught the plague; for they would immediately adopt an attitude of utter hopelessness, and, by giving in this way, would lose their powers of resistance. (Thucydides quoted from Clark, 1995, p.221)

41

Could the pineal play a role in mediating the known effects of mood on the immune system?

Melatonin has been recognized, in recent years, to be a potent antioxidant. Antioxidants are known to counter damage to the immune system from free radicals. Damage from free radicals is implicated in immune malfunction and several other pathological processes. It should be noted that while melatonin is synthesized mainly in the pineal organ in humans and other mammals (with smaller amounts produced in the retina) this molecule is also found in invertebrates and plants. The indole amine is even found in some bacteria. In these life forms (which obviously lack a pineal) it is thought that its role as an antioxidant is an important physiological function (Reiter et al, 2003).

The role of melatonin as an antioxidant provides a rationale for use of melatonin as an anti-aging supplement, since free radicals are implicated in several pathological processes associated with aging, including cardiovascular disease and weakening of the immune system (evidenced by an increased incidence of various cancers and increased susceptibility to infections with age). As mentioned, taking melatonin for these reasons is not without risk, and there is little evidence that taking melatonin supplements is good for the health there is considerable difference between optimizing endogenous production of melatonin and taking exogenous supplements.

The antioxidant properties of melatonin have been clearly demonstrated by numerous studies since the 1990s. It appears that melatonin acts in several ways in this regard. The molecule acts as a direct scavenger of free radicals in addition to potentiating other antioxidants (Reiter, et al, 2003). It also lowers free radical generation by increasing the efficiency of mitochondrial oxidative phosphorylation and

42

reducing electron leakage. In addition, melatonin stimulates various anti-oxidative enzymes. Other studies have shown an association between low melatonin levels and the development of various cancers (breast, lung, brain, skin and kidney). There is also evidence that exogenous melatonin supplementation reduces mortality from a range of cancers (Mills, et al, 2005).

THE PINEAL AND ELECTROMAGNETIC FIELDS A more controversial area of possible pineal function relates to magnetic fields. The main proponent of the theory that the pineal functions as a magnetic sense organ is the American scientist Robert Becker. In his book Cross Currents (1990) Becker presents evidence that the pineal is a component of a poorly recognized magnetic organ in humans and in other animals. This magnetic organ senses the earths geomagnetic field, according to Becker, and is affected also by artificial magnetic fields caused by human activity.

While this aspect of possible pineal function is speculative, it may explain findings, from the 1970s, that the pineal organ is involved in our sense of direction. It is generally accepted that such a magnetic sensitivity does exist in birds, and that the pineal is involved in migratory behavior in birds. Though controversial, this is another potentially fruitful area of interest for future research.

43

CONCLUSION
Research over the past fifty years has proved beyond doubt that, far from being a useless vestigial organ, the pineal is an important part of the brain. The pineal is an integral part of the endocrine system, producing the neurohormone melatonin which has effects on sleep, immune function and sexual function. In addition the pineal may play a magnetosensory role in humans, as it is known to in birds, and may also be involved in regulation of mood (along with many other parts of the brain). Research in the future promises to provide more insights into the many mysteries of the pineal organ.

REFERENCES
Adeloye, A. and Felson, B. (1974) Incidence of Normal Pineal Gland Calcification in Skull Roentgenograms of Black and White Americans. American Journal of Roentgenology. 122 (3) pp 503-507

Arendt, J. (1995) Melatonin and the Mammalian Pineal Gland.

Becker, R. (1990) Cross Currents. Bloomsbury: UK

Clark, W. (1995) At War Within. Oxford University Press: USA/UK

Daramola, G and Oluwu, A. (1972) Physiological and Radiological Implications of a Low Incidence of Pineal Calcification in Nigeria. Neuroendocrinology. 9 (1) pp 41-57

Hadley, M. (1984) Endocrinology. Prentice-Hall: USA

Ham, A. (1957) Histology. Lippincott: USA/Canada

44

Kandel, E. (ed) (1995) Essentials of Neural Science and Behavior. Appleton & Lange: USA

Kappers, A (1981) Anatomy and Biochemistry, chapter in The Pineal Gland, volume 1 (Reiter, R, editor). CRC: USA

Kolb, B. and Whishaw, I. (1990) Fundamentals of Human Neuropsychology. Freeman: USA

Kotulak, R. (1996) Inside the Brain. Andrews and McMeel: USA

Mills E, Wu P, Seely D, Guyatt G. (2005) Melatonin in the treatment of cancer: a systematic review of randomized controlled trials and meta-analysis. Journal of Pineal Research. 39(4):360-6.

Mugondi, S and Poltera, A. (1976) Pineal Gland Calcification in Ugandans: a radiological study of 200 isolated pineal glands. British Journal of Radiology. 49, pp 594-599

Murphy, N. (1968) Carotid Cerebral Angiography in Uganda: a review of 100 consecutive cases. East African Medical Journal. 45, pp 47-60

Norden, M. (1996) Beyond Prozac. Harper-Collins: UK

Reiter, R. (1984) The Pineal Gland. Raven: USA

Reiter, R.,Tan, D., Mayo, J, Sainz, R., Leon, J. and Czarnocki, Z. (2003) Melatonin as an antioxidant: biochemical mechanisms and pathophysiological implications in humans. Acta Biochimica Polonica. 50 (4) 1129-1146

Relkin, R. (1983) The Pineal Gland. Elsevier Biomedical: USA

45

Snell, R. (1980) Clinical Neuroanatomy. Little, Brown: USA

Wurtman, R. (1980) Diseases of the Pineal Gland, chapter in Harrisons Principles of Internal Medicine (9th edition). Isselbacher, K., Adams, R., Braunwald, E., Petersdorf, R., Wilson, J. (editors) McGraw-Hill: USA