Serotonin & the Pineal Gland

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SEROTONIN & THE PINEAL GLAND


Pineal Gland By Charly Groenendijk
The Netherlands
Oct 9, 2001 (updated March 11, 2003)


The Serotonergic System, the Pineal Gland & Side-Effects of Serotonin Acting Anti-Depressants -Part 1

Go to Serotonin & the Pineal Gland -Part 2
REFERENCE

The content of this article is based on and written in accordance with accepted theories in Bio-Psychiatry and should therefore be perceived as another theory.

Take notice that also non SSRI anti-depressants (such as SNRI's targeting the neurotransmitter nor-epinephrine (nor-adrenaline) and even Ritalin) may interact (primary or secondary) with the serotonergic system in the brain, causing serotonin deficiency symptoms.

1. Introduction: Neurons & Neurotransmitters
There are billions of working cells in our brain called Neurons and great variety in the kind of brain cells or neurons, with each group representing a specific cluster of functions. Neurons communicate with similar neurons by firing molecules from its nerve endings to the receiving nerve endings of the other neuron. The nerve endings of the firing part of the neuron are called axon terminals and the nerve endings of the receiving part of the neuron are called dendrites. The end of the axon terminals are called synapses. The synaptic cleft is the space where synapses and dendrites meet each other and where all the activity takes place. Each neuron is able to receive and fire molecules simultaneously. The molecules fired in the synaptic cleft are called neurotransmitters. Situated at the end of the axon terminals of the firing part of the neuron, the synapses work like "ball throwers." The dendrites of the receiving part of the other neuron, work like "catcher's mitts." They use receptor-molecules, or receptors, to capture the "thrown" neurotransmitters. (See Picture)

Re-Uptake
Once one neuron is firing neurotransmitters from it's synapse to the receiving dendrite of the other neuron, it is critically important that the "mis-fired" neurotransmitter left overs must be removed from the synaptic cleft. Any neurotransmitter which is not removed from the synaptic cleft, prevents further neurotransmitters from getting through. Re-uptake, the process of removing neurotransmitters after firing or release, allow these neurotransmitter left overs to be recycled for further use. Re-uptake is carried out by "transporter proteins" which bind to the mis-fired neurotransmitter and carry it across the plasma membrane back into the synapse of the firing neuron.

Medication classified "Re-Uptake Inhibitors" act on these transporter proteins and thereby inhibit the re-uptake of neurotransmitters back into the synapse of the firing neuron. SSRI-AntiDepressants or Selective Serotonin Re-uptake Inhibitors, belong to this class of medication. Each group of neurons fire specific neurotransmitter-molecules. The neurotransmitter Serotonin, also known as 5-Hydroxy-Tryptamine (5-HT) is such a molecule. SSRI-AntiDepressants inhibit the re-uptake of serotonin what means that more serotonin will be fired from synapse to dendrite in the synaptic cleft of every communicating serotonergic neuron in the brain.

2. The neurotransmitter "Serotonin"
In the brain, serotonin is synthesized from the amino acid precursor "Tryptophan". By enzymatic interaction, tryptophan converts into 5-HTP and eventually into serotonin. (see image) This neurotransmitter belongs to the group of serotonergic neurons which make the Serotonergic System in the brain. Levels of serotonin are highly concentrated in the Raphe Nuclei. Raphe Nuclei are present in the Medulla and Pons, 2 structures which are part of the Brainstem. From the Raphe Nuclei in the pons of the brainstem, also called "Rostral Raphe Nuclei", serotonin pathways project through parts of the Limbic System (like the Thalamus and Hypothalamus) into the Forebrain. (See Picture)

2.a. Serotonergic functioning
If you would believe the overwhelming advertisements of the pharmaceutical companies, you would think that serotonin primarily regulates mood. In fact, serotonin regulates a lot of other activities in the brain and body. In 1948, Maurice Rapport, a haematologist, found that serotonin tended to make blood form clots, and it tended to be a muscle- as well as a vasoconstrictor. Next to be a muscle- and vasoconstrictor, serotonin plays an important role in sleep, appetite, memory, aggression, sexual behaviour, cardiovascular activity, respiratory activity, motor output, sensory and neuroendocrine function, but most important, perception! Since 1988 the serotonin hype brought us several SSRI-AntiDepressants all stimulating this neurotransmitter. For about 11 years now, Dr. Ann Blake Tracy (Prozac: Panacea or Pandora?), persistently warns the public against raising serotonin levels. Doctor Tracy has taught us that an increase in serotonin produces rushes of insulin dropping sugar levels and chemically inducing hypoglycaemia (low blood sugar) in this way. Furthermore it has been established that too much serotonin damages blood vessels, particularly in the lungs, and may also harm heart valves. This would be due to the fact that serotonin is a powerful vasoconstrictor.

Affecting Mood or Mind?
But most alarming is the serotonin and perception connection. Doctor Tracy as well as other sources described how the hallucinogenic drug LSD strongly acts on this neurotransmitter serotonin. The numerous examples of human LSD experiences have learned us that serotonin plays a major part in perception, our sense of reality, how we experience our in- and outside world! Other examples of drugs acting on the serotonergic system are PCP and MDMA (Ecstasy). Most of the readers will recognize also these serotonergic drugs for their capability to produce "an altered state of consciousness" in human beings. In the way that the serotonergic system responds to serotonergic drugs, we may conclude that this system is heavily involved in the determination of ones perception and therefore ones thought processes and emotions. The advertisements from the pharmaceutical companies, promoting elevated serotonin levels as were they purely mood lifting, therefore seem to be rather misleading then informative. SSRI-AntiDepressants are to be considered mind-altering drugs and not primarily mood-altering.

In all these years since 1988, scientists are still not sure why serotonin boosters seem to "alleviate" depression. They assume that low serotonin levels could be a possible cause of endogenous depression, but it's still just a theory and not a proven fact! New research present us a different view on serotonin, which may not even have that connection with mood as previously thought. By experimental research, scientists discovered that a new drug, code-named MK-869, blocked a neuropeptide called " Substance P." By blocking this neuropeptide, people became less depressed. An interesting fact was, that blocking substance P did not affect the function of serotonin! This raises new concerns about the involvement of serotonin in mood and/or depression.

"But why do I hear people talking about benefits from these SSRI-AntiDepressants?", you might want to ask in this stage. "They surely must work somehow don't they?" The answer is yes, they "work" somehow, but not in a very proper way. The mechanism of action on serotonergic neurons implies a lot of other neuro- endocrine responses. What actually happens when you increase serotonergic neuronal activity or elevate your serotonin levels is this: the stress hormones "Cortisol" & "Adrenaline" (Epinephrine) in the brain and body are triggered by increased serotonergic activity or elevated serotonin levels. It is a natural reaction from the body to combat the excessive serotonin levels. These released hormones, cortisol and adrenaline, are secreted from the "Adrenal Glands." They give the human personality a boost, producing a euphoric state, which can last for a prolonged period of time. In this manner SSRI-AntiDepressants initially produce the deceptive results the doctor and "patient" are both expecting. *

If a patient continues to ingest a particular SSRI-antidepressant over a prolonged period of time, eventually the bodies Adrenal Glands may lose their efficiency and "Adrenal Exhaustion Syndrome" will be the end result. Adrenal Exhaustion causes levels of adrenaline initially to fall and levels of cortisol to rise. Ultimately, also cortisol levels fall. When untreated, Adrenal Exhaustion will lead to seriously declining physical health. Many (former) SSRI-AntiDepressant users reported fatigue as a long term side-effect or were diagnosed with "Chronigue Fatigue Syndrome." People suffering from stress are generally diagnosed with this disorder. Symptoms range from simple exhaustion to much more complex problems that are secondary to excessive output of adrenal hormones in the bloodstream, leading to Adrenal Exhaustion. Unlike the other hormones, it takes a long time before the Adrenal Glands have their adrenaline levels restored. Could we say that the SSRI-AntiDepressant "works" by slowly excavating the body's Adrenal Glands?

* [ Actually, when a family doctor (GP) or psychiatrist is observing a patient in a "euphoric" state of being, this should ring warning bells immediately! The drug induced (iatrogenic) conditions Akathisia & Mania are well documented in the medical litarature. Drug induced Mania, an abnormally elated mental state, typically characterized by feelings of euphoria, racing thoughts and talkativeness, is a "forerunner" of Akathisia, a neurologically driven agitation ranging from mild leg tapping, feeling "caffeinated" to severe panic, an extreme manic state and hyper-sensitivity of the nervous system. Akathisia can lead to suicidal, aggressive and/or homicidal thoughts and behaviours. When a doctor or psychiatrist is observing symptoms of mania and/or akathisia in a patient, SSRI-AntiDepressant use should be discontinued immediately! The pharmaceutical companies are well informed regarding above mentioned conditions and the capacity of their antidepressant inducing these symptoms. Therefore it is strongly advised to medical professionals, physicians, to monitor a patient very closely after prescription of (SSRI) anti-depressant treatment. In the field of Bio-Psychiatry it was a conventional common thought that hypothalamic-pituitary-adrenal (HPA) system dysregulation/hyperactivity (and thus excessive secretion of cortisol) played an important role in the pathophysiology of depression and that normalization of HPA axis hyperactivity could be achieved by (SSRI) anti-depressant treatment, and thus relief of depression. However, a study and a case report involving the non-SSRI antidepressant Remeron (mirtazapine) and a review show us that nor amelioration of HPA system dysregulation, nor reduction of cortisol secretion in depressed patients is correlated with relief of symptoms of depression. See: (1), (2), (3). Furthermore, a study developed by D. Jezova & R. Duncko, Laboratory of Pharmacological Neuroendocrinology, demonstrated that repeated SSRI-antidepressant treatment in healthy men does not inhibit, but enhances stress-induced pituitary hormone release (neuroendocrine activation). Cortisol levels failed to be modified by antidepressants. A simple search through available PubMed articles uncovers clearly that SSRI-antidepressants not only fail to modify cortisol, but actually stimulate/increase cortisol release. See: (1), (2), (3), (4), (5), (6). Initially the rise in cortisol & adrenaline (secreted from the Adrenal Glands) may create the illusion of a patient making progress in his/her situation, but a potential tragedy may be surfacing very soon. It is very well known that (SSRI-AntiDepressant induced) increased cortisol secretion can lead to violent suicidal behaviour.
(I would like to encourage you to use your discernment when viewing antidepressant involved suicide/homicide/violence cases represented by the media. In the section casualties of this website, these cases are carefully stored up to be a "silent" witness for the future, in order to testify regarding the devastating & powerful destructive effects these "legal drugs" exercised on children, adolescents and adults, not discriminating between men and women). ]

The Serotonin-Cycle: beaconing of conscious awareness and dream sleep?
One of the first significant discoveries about the serotonergic system in the brain was that it's activity was dramatically altered across the sleep-wake cycle. Serotonergic activity gradually decreases as one becomes drowsy and enter slow-wave sleep. An overall slowing of serotonergic activity is observed during slow-wave sleep known as non-REM sleep. During REM sleep (Rapid Eye Movement-the original dream sleep), serotonergic activity falls completely silent. Serotonergic activity returns to it's basic level several seconds prior to the end of REM sleep. REM sleep occurs in roughly 90-100 minute cycles, alternating with non-REM sleep (around 4 to 5 times during sleep). During non-REM sleep, there is lots of movement, but during REM sleep, only the eye muscles move. REM-dreaming turns on neurons in the medulla of the brainstem that inhibit all other motor activity. In this way it prevents the dreamer from sleepwalking and to act out his/her dreams in real time.

Another significant discovery was that, when during REM sleep the serotonergic neurons in the brainstem were "off" (silent), cholinergic neurons in the brainstem were "on" (firing)! Cholinergic neurons fire the neurotransmitter "Acetylcholine." Acetylcholine not only plays an important role in dreaming, but also in long-term memory processes. In the brainstem, the cholinergic "REM-on" neurons can only trigger REM sleep (and thus dreaming) when the serotonergic "REM-off" neurons are inactive. This happens because, in the brainstem, the serotonergic neurons inhibit the cholinergic neurons whilst we are awake. When, in the brainstem, the serotonergic neurons release their inhibitory constraint, only then, the cholinergic brainstem neurons will be able to get active, triggering the REM-dream sleep. Both the REM-on and the REM-off cells are localized in the brainstem. These brainstem mechanisms work as an "oscillator", which controls the transitions from waking to sleeping and further controls the REM/non-REM cycle, which occurs 4 to 5 times during sleep.

Now at this moment you might ask yourself, how it is possible that so many individuals report bizarre vivid lifelike dreams whilst on serotonin boosters, when an active serotonergic system suppresses REM sleep, and thereby dreaming? Serotonergic suppression of REM sleep in humans by acute dosage of SSRI-AntiDepressants was indeed confirmed. (see article) This is what Dr. Tracy is also been telling us for many years in her book. The PubMed article discusses rebound of REM sleep after abrupt withdrawal from an SSRI-AntiDepressant, but it still doesn't answer the question how it is possible that individuals are experiencing disturbing dreams and nightmares whilst they are taking an SSRI-AntiDepressant over a prolonged period of time. When I delved deeper into this matter I discovered some interesting facts. Although there is an important link between REM sleep and dreaming, they are in fact doubly dissociable states. That is, REM can occur without dreaming and dreaming can occur without REM. Although REM is triggered from the brainstem, it alone will not result in dream states. Dreams require input from the forebrain and structures in the limbic system. The forebrain mechanisms are the final common path to dreaming. The brainstem is just one of the many arousal triggers that can activate these forebrain mechanisms. Although REM sleep is controlled by the brainstem, dreaming seems to be controlled by these forebrain mechanisms. It is now acknowledged that REM sleep is not necessary for dreaming, that dreaming can also occur during non-REM sleep, and that dream-like experiences can even be elicited during quiet wakefulness! The controversial human reports of very vivid lifelike dreams whilst taking an SSRI-AntiDepressant could therefore be explained as existing outside and independent of the REM (dream) sleep! But, -now that we know that the forebrain is the final common path to dreaming, and SSRI-AntiDepressants suppress the brainstem's REM arousal system (which normally activates forebrain dreaming)- what kind of arousal triggers are then responsible for the activation of forebrain dreams during use of SSRI-AntiDepressants?

Forebrain Nightmares and Forebrain Seizures
An even more exciting discovery was that dreaming can also be induced by focal forebrain stimulation and by complex partial forebrain seizures during non-REM sleep, without the involvement of the brainstem's REM mechanism! There is a causal link between epileptic activity and recurring nightmares during non-REM sleep. This was demonstrated by neurosurgeon and researcher Wilder Penfield, who was able to reproduce these anxious experiences artificially in the form of waking "dreamy state" seizures. The causal link between forebrain seizures and recurring nightmares was confirmed by the fact that both the underlying seizure disorder and the nightmares responded to anticonvulsant therapy.

Here is an example of a recurring nightmare, caused by epileptic activity in the forebrain:
The patient [35 year old woman with idiopathic complex-partial seizures] reported a recurrent dream about her [dead] brother ... which has reappeared several times. The dream is as follows: "I am walking down the street. I meet him. He is with a group of people whom I know now. I feel that I will be so happy to see him. I say to him, `I'm glad you're alive,' but he'll deny that he is my brother and he'll say so, and I'll wake up crying and trying to convince him."' Electroencephalography revealed a poorly defined right anterior temporal / right temporal spike focus which appeared with the onset of drowsiness and light sleep (Epstein & Ervin 1957, p. 45).

Could it be that the bizarre vivid lifelike dreams, reported by SSRI-AntiDepressant users are epileptiform of nature? Notice the "poorly defined spike focus." Could it be that this is epileptic activity which remains undiscovered because it is barely detectable? Standard tests for epilepsy included?

3. The Pineal Gland
The Pineal Gland -also called the epiphysis- looks like a miniature pine cone and is situated in the middle of the brain beneath the two brain halves, surrounded by the ventricles, under the roof of the corpus callosum (cross-beam connecting the 2 brain halves). (see picture) This active organ has, together with the Pituitary Gland (see picture), the next highest blood circulation after the kidneys. It is not protected by the blood-brain barrier and therefore makes this gland fragile to any substance entering the bloodstream. It is, for instance, very sensitive to fluoride.

Another factor involved in affecting the Pineal Gland can be excessive high or even toxic levels of an SSRI-AntiDepressant in the bloodstream. Certain individuals have a metabolic deficiency in the metabolism of anti-depressant medication. In the liver, a group of enzymes named " cytochrome P-450" enzymes, particularly the "CYP2D6 enzymes" of this group of enzymes, metabolise SSRI-AntiDepressants. When not properly metabolised, because one has a metabolic deficiency, a daily therapeutic dose can build up to excessive high or even toxic levels in the bloodstream. Hence, the Pineal Gland would be an easy target, since it is not very well protected by the blood-brain barrier. It is it's connection to serotonin what makes this organ so very interesting.

3.a. The Pineal Gland-Serotonin connection
Nicholas Giarmin, a professor of pharmacology and Daniel Freedman, a professor of psychiatry, confirmed that the human brain manufactures serotonin at various sites in the brain. For example, in the Thalamus, they discovered 61 nanograms of serotonin per gram of tissue; in the Hippocampus, 56 ng.; in the Central Gray Section of the Midbrain, they found 482 ng. But in the Pineal Gland, they found 3140 ng. of serotonin per gram of tissue. The Pineal Gland was unmistakably the richest site of serotonin in the brain! This discovery implicates the Pineal Gland as an important site of serotonergic activity.

The neurohormone Melatonin & the Endocrine System
One of the neurotransmitters secreted by the Pineal Gland is Melatonin, also known as N-Acetyl-5-Methoxy-Tryptamine (NA-5-MT). In the Pineal Gland, serotonin converts into melatonin by enzymatic interaction. Melatonin is also an important hormone to the body, that's why it is called a neurohormone. It is necessary to regulate the function of all organs of the Endocrine System in the body. The organs or glands of the endocrine system are: the Pituitary Gland, situated in the brain; the Thyroid + Parathyroid Glands; the Thymus; the Pancreas; the Ovaries/Testes (see image). All of these endocrine organs/glands secrete their hormones to the blood. The Pituitary Gland stimulates the secretion of these hormones, while the Pineal Gland apply the brakes on them through it's neurohormone melatonin. If the endocrine organs/glands release too much of their hormones, for instance when we are stressed, then the Pineal Gland releases melatonin to counteract these hormones. Also serotonin gets released when stress is involved. The increased serotonin triggers the release of adrenaline, which allows the body to work through the stress.

The Pineal Gland is a magneto sensitive organ, what means that it is sensitive to electromagnetic fields (EMF). It is sensitive to electromagnetic waves from computer monitors, cellular phones, microwave ovens, high voltage lines, etc.. Electromagnetic fields suppress the activity of the Pineal Gland and reduce melatonin production. EMF also affect serotonin.

The neurohormone Melatonin & the Eye-SCN-Pineal Gland Axis
The Pineal Gland is also a photosensitive organ, what means that it is sensitive to light. It normally releases melatonin when it no longer receives light impulses. Just like serotonin, also melatonin has it's own day & night cycle (circadian rhythm) which begins where the cycle of serotonin normally ends. When serotonin reaches it's lowest level at night (in the dark) during slow wave sleep, the Pineal Gland starts to convert it's store of serotonin into melatonin to be released prior to REM sleep. Melatonin has it's peak around 02:00 AM. During daytime, the daylight inhibits the release of melatonin. This works as follows: when, during daytime, light reaches the eyes, then it's presence gets translated into nerve impulses, which travel through the optic nerve between the eyes and a region of the Hypothalamus called the "Suprachiasmatic Nucleus" (SCN). (see picture) The SCN in it's turn sends it's nerve impulses to the Pineal Gland. These impulses inhibit the Pineal Gland's production of melatonin until it gets dark, when it's to be released again.

Melatonin is not only present in the brain and body but also in the eye! One has speculated whether or not high melatonin levels in the eyes during daylight exposure, may bring damage to them over time. Visual/eye problems (light sensitivity, spots, blurred vision) are other symptoms, frequently reported by (former) SSRI-AntiDepressant users. I questioned myself if these problems could be related to elevated melatonin levels in the eye. When serotonin accumulates in the Pineal Gland, on account of an SSRI-AntiDepressant, then it would come under pressure to produce more melatonin out of the excessive amounts of serotonin. Hence, during daytime, melatonin levels in the eyes would be significantly higher then normally would occur... But, I had to revise this hypothesis. In a PubMed study, SSRI-AntiDepressants were found not to elevate melatonin levels in humans. Although "Luvox" and "Paxil" increases melatonin to a more or lesser amount, apparently this seemed not to be the case for the other SSRI-AntiDepressants. However, since the Pineal Gland does contain a complete map of the visual field of the eyes, could there be a correlation between visual/eye problems and a dysfunctional Pineal Gland?

A case, noted by Dr. Berman, could give us some more insight into this matter:
A child was brought to a German clinic suffering from eye trouble and headaches. He was five years old and very mature, and apparently had reached the age of adolescence. He was abnormally bright mentally, discussing metaphysical and spiritual subjects. He was strongly group-conscious and only happy when sharing what he had with others. After his arrival at the clinic, he rapidly grew worse and died in a month. An autopsy showed a tumour of the pineal gland. - Berman, Louis, M.D., The Glands Regulating Personality, p. 89.

Could it be that the visual/eye problems (light sensitivity, spots, blurred vision), frequently reported by (former) SSRI-AntiDepressant users, are caused by some element of Pineal Gland dysfunction?

Continue... Serotonin & the Pineal Gland -Part 2


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