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seeking: eros and the pineal gland

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Located almost in the center of your brain is a small projection of tissue called the pineal gland. It is shaped like a tiny pine cone, roughly a quarter of an inch long, and weighs about a tenth of a gram. Despite its small size, the pineal gland contains enormous amounts of serotonin, a physiologically active biogenic amine and chemical neurotransmitter. But pineal cells are not neurons and do not use serotonin for neurotransmission. Instead, pineal serotonin functions as a substrate for the enzymatic production of other biologically active molecules.


Nevertheless, the pineal gland is intimately related to the broad network of neurons that do release serotonin as a chemical messenger, An estimated several thousand of these serotonergic neurons are in the human brain. Their cell bodies are located almost exclusively in the midbrain, the pons and the medula oblongata. Some of their axons descend to ennervate the gray matter of the spinal cord; others ascend to the brain and terminate in the thalamus, limbic forebrain, and hypothalamus. Related by a common biogenic amine, the pineal gland and the serotonergic neurons play an important role in the regulation of mood, behavior and consciousness.




A unique biochemical mechanism exists within the human pineal gland. A pair of naturally occuring pineal enzymes, hydroxy-indole-O-methyl transferase (HIOMT) and indole-N-methyl transferase (INMT), are capable of converting serotonin into a number of potent hallucinogens. Regulated by a variety of neuroendocrine mechanisms, these enzymes normally act on specific substrates and function as catalysts in the formation of biogenic amines. However, if they get out of phase with their normal substrates and act on pineal serotonin, they form potent psychoactive compounds within the human brain.


Interestingly enough, pineal catabolism can be intentionally shifted toward the production of these endogenous hallucinogens by a simple manipulation of amine metabolism. If you increase the concentration of pineal serotonin and block its normal enzymatic inactivation, it becomes a substrate for other pineal enzymes, like HIOMT and INMT. As their names imply, HIOMT and INMT are methyl transferase enzymes. They catalyze the transfer of a methyl group from one compound to another. As these enzymes add methyl groups to the indole-oxygen and amino-nitrogen positions, serotonin is converted into 5-methoxy-N,N-dimethyltryptamine, a relatively unknown but extremely potent hallucinogen.









Before attempting any manipulation of biogenic amines in the human nervous system it is essential to have a thorough understanding of the blood-brain barrier (BBB). The BBB is a selective barrier, which isolates the brain from substances circulating in the bloodstream. When blood composition fluctuates, the BBB functions as a protective insulator and attempts to maintain a relatively constant internal environment for neural cells, The BBB is basically a barrier to the diffusion of molecules between the bloodstream and brain tissue. Existing at capillary levels this barrier can be understood by examining the capillary junctions and the nature of lipids and proteins within the cell membrane.




Another important factor in the barrier to diffusion is the nature of the endothelial cell membrane. The membrane consists of phospholipid molecules (lipids) and specialized proteins. The lipids form the structural framework of the membrane and an anchoring structure for the various protein molecules.




Each lipid molecule has a polar head and two non-polar tails. The polarity in the head results from the molecular interaction between the oppositely charged phosphate and nitrogen groups. The resulting dipole makes this part of of the molecule polar and, therefore, water soluble. It is called the hydrophilic, or water-loving, portion of the lipid molecule. In contrast, the two tails of each lipid molecule are non-polar and water insoluble. They are composed of long-chain fatty acids which are hydrophobic, or water-hating, in nature. The tails are joined to a backbone molecule which, in turn, is attached to the polar head.


Because they each contain a hydrophilic and hydrophobic end, lipid molecules naturally form a bilayered membrane. The polar, water-soluble heads point toward the water on the inside and outside of the cell, while the non-polar, fatty-acid tails point away from water and toward the membrane interior. The resulting bilayer of lipid molecules contains an oily inner core, It functions as a selective barrier permeable to lipid-soluble substances and impermeable to polar, water-soluble substances.




One important factor in the BBB is the tightness of junctions between the cells of the brain capillaries. Throughout the body, capillaries are composed of endothelial cells — a single layer thick — which form a thin membrane between the bloodstream and the surrounding tissue. In the general capillaries of the body, the cells circle upon themselves but leave small gaps between adjacent cells. Water-soluble substances can easily diffuse through these gaps into the surrounding tissue.


In the brain capillaries, however, the endothelial cells circle upon themselves and form a barrier to diffusion. Adjoining edges are overlapped and fused, creating extremely tight junctions between cells. Substances that might easily diffuse through the gaps in general capillaries are blocked by the close connections between brain endothelial cells. The first factor, the tightness of these junctions, not only prevents intracellular diffusion but creates an extended cell membrane along the length of the brain capillaries.




Various proteins are also associated with the membrane. They may support either the inner or the outer surface. They may be contained partially within one of the surfaces, or they may extend completely through the lipid bilayer. Some of these proteins are highly specialized molecules that capture specific substances from the bloodstream and transport them through the lipid barrier. Those proteins that extend through the membrane may actually transport substances through pores within themselves. Other proteins may combine with a substance at one membrane surface, diffuse across the lipid bilayer, and dissociate from the substance at the other surface.




Different protein molecules transport different substances necessary for normal brain function (amino acids, sugars, salts). Each of the amino acid carrier molecules has specificity for either basic, acidic, or neutral amino acids and is also selective toward the size of the molecule — clearly differentiating between large and small amino acids. For example, one type of carrier protein recognizes, captures and transports only the large neutral amino acids, tryptophan, leucine, isoleucine, valine, tyrosine, and phenylalanine — all large neutral amino acids — compete for this carrier. Transport is proportional to blood concentration. If one amino acid is proportionally higher in concentration it is preferentially transported through the membrane.









Attempting to increase the amount of serotonin in the human nervous system might initially seem to require a supply of serotonin. How simple it would be if brain concentrations could be increased just by the ingestion of pharmaceutical serotonin or, for that matter, any of the many foods which contain serotonin. Unfortunately, this is not the case. Brain levels are not increased by dietary supplements; blood levels are elevated, but the BBB effectively blocks the diffusion of serotonin into brain tissue.


In the bloodstream, at physiological PHI the serotonin molecule exists in the ionized form. An electrical charge from the hydroxy group on the indole ring creates polarity in the molecule. As a result, serotonin has poor lipid solubility; it is more soluble in water than in oils or lipids. It can neither dissolve in nor diffuse through the lipid bilayer of the BBB and has no specific carrier molecule. Therefore, dietary serotonin can neither leave the bloodstream nor enter brain tissue.




Cerebral serotonin is normally synthesized from l-tryptophan, its necessary precursor. Tryptophan is an essential amino acid. That is, it cannot be synthesized in the human body, it must be obtained from ingested protein or amino acid supplement. Unlike serotonin, dietary tryptophan can penetrate the BBB and enter brain tissue.


The process begins with digestion. Dietary tryptophan is absorbed into the bloodstream, where most of it circulates bound to albumin, a plasma protein. Tryptophan is unique; it is the only amino acid that binds to plasma proteins, The other large neutral amino acids are completely unbound.Valine, leucine, isoleucine, tyrosine, and phenylalanine all circulate in free form within the bloodstream. But most tryptophan is bound. Only 10 percent circulates unbound in a free form and, naturally, only free, unbound tryptophan is able to leave the bloodstream. At the BBB the unbound tryptophan competes with the other large neutral amino acids for the specialized carrier molecules that transport these amino acids into the brain. Transport is proportional to blood concentration, Therefore, the amount of tryptophan that penetrates the BBB is ultimately determined by the ratio between free, unbound tryptophan and competing amino acids.




The ratio between tryptophan and the other large neutral amino acids is easy to manipulate. Dietary supplements of l-tryptophan are available over the counter at any pharmacy. Ingestion of several grams increases the amount of bloodstream tryptophan without raising the levels of competing amino acids. However, most of this supplemented tryptophan binds to blood serum proteins. Only 20 percent circulates in the free, unbound form. And, since only the unbound form is able to penetrate the BBB, the proportion of free-to-bound tryptophan becomes quite important.


Interestingly enough, both the ratio of tryptophan to competing amino acids and the proportion of free-to-bound tryptophan can be manipulated by the ingestion of a candy bar. Carbohydrate consumption stimulates the release of insulin from the pancreas. Insulin, in turn, lowers the plasma concentration of glucose and simultaneously enhances the uptake of branched-chain amino acids into muscle. These are the same amino acids which normally compete with tryptophan for transport through the BBB. As their blood concentration decreases, tryptophan continues to circulate in both the free and bound form. But insulin affects this equilibrium as well and releases tryptophan from its binding sites and the albumin molecules. Free, unbound tryptophan increases in concentration, achieves the competitive advantage at the BBB, and is preferentially transported through the endothelial cell membrane by carrier proteins.




After penetrating the BBB, tryptophan is taken up by the paraneuron cells of the pineal as well as the neurons of the serotoneoic pathway. Once inside, tryptophan diffuses to intracellular sites rich in the metabolic enzymes which convert it into serotonin.


The conversion is a two step process. In the first step, an enzyme called tryptophan-5-hydroxylase adds a hydroxyl group to the 5 position on the indole ring. Then a second enzyme called aromatic amino acid decarboxylase removes the carboxyl group from the amino acid side chain. The product, 5-hydroxytryptamine, is commonly called serotonin.


Increased amounts of serotonin are noticeable in brain tissue within two to three hours after the ingestion of a candy bar and a couple of grams of l-tryptophan. Employing a simple manipulation of blood chemistry, this method circumvents the BBB and increases the concentration of serotonin in the human nervous system.




Normally the major pathway in the catabolism of serotonin involves inactivation by the mitochondrial enzyme monoamine oxidase (MAO). In a process called oxidative deamination, MAO converts as much as 80 percent of the body's serotonin into a physiologically inactive metabolite. As serotonin binds to the enzyme's active sites MAO removes the amine function and renders the molecule harmless and ineffective.


MAO is an important catabolic enzyme in the human body. It is the major enzyme involved in the breakdown and inactivation of serotonin. Any drug that interferes with the function of this enzyme is, by definition, an MAO inhibitor.




MAO inhibitors can be classified by long-term or short-term inhibition. The long-term MAO inhibitors bind irreversibly to the enzyme and therefore, exert their effects long after the drug is cleared from the body. New MAO protein must be synthesized in the cell body in order to terminate the inhibition. This usually requires a period of ten to twenty days. [This irreversible MAO inhibition was presumably the biochemical basis of the McKenna brothers' 3-week psychedelic voyage in the Amazon in 1971, as described in True Hallucinations. — Ed.] In contrast, a short-term MAO inhibitor is reversible on the order of three to six hours. The harmala alkaloids, harmine and harmaline, for example, are especially potent, short-term MAO inhibitors. A small oral dose (25-50 milligrams) temporarily prevents physiologically active amines, like serotonin, from binding to the active site of the MAO molecule and undergoing deamination. For three to six hours, the harmala alkaloids interfere with the function of MAO before their action is reversed and MAO activity restored.




A combination of l-tryptophan and a short-term MAO inhibitor creates a favorable condition for the formation of psychoactive tryptamines within the human pineal gland. Tryptophan loading produces a significant increase in brain tryptophan levels and a subsequent increase in serotonin levels. When its major inactivation pathway is blocked by MAO inhibition, serotonin becomes a substrate for other pineal enzymes. Two methyltransferase enzymes, HIOMT and INMT, are capable of converting excess serotonin into a number of psychoactive derivatives.


HIOMT, localized exclusively within the pineal gland, specifically catalyses the transfer of a methyl group to the oxygen located at the five position an the indole ring. In other words, HIOMT converts a 5-hydroxy-indole into a 5-methoxy-indole. This enzyme converts serotonin, 5-hydroxytryptamine, into a psychoactive compound called 5-methoxytryptamine. In turn, this compound becomes a substrate for INMT, another pineal methyltransferase enzyme.


INMT specifically catalyses the transfer of methyl groups (one at a time) to the amine nitrogen on an indole side chain. The resulting monomethyl intermediate, 5-methoxy-N-methyltryptamine, is also psychoactive, but it is quickly converted to the dimethyl derivative by INMT. The final molecule — endogenously produced in the human pineal gland — is 5-methoxy-N,N-dimethyltryptamine, a relatively unknown but extremely potent hallucinogen.

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Tryptophan and 5-Hydroxy Tryptophan – The Key to Connection


The amino acid tryptophan, a normal constituent of food, is the basic building block not only of serotonin, but also of tryptamines, such as DMT. As such, tryptophan is critical to the chemistry of connection. As already discussed (see Chapter 7) tryptophan deficiency leads to depression, while supplementing tryptophan has proven an effective anti-depressant.


As far as promoting a natural state of connection is concerned the objective is to make sure that the brain and nervous system has an adequate supply of this vital amino acid. This not only depends on your daily intake of tryptophan, but also your intake of B vitamins.


Unfortunately tryptophan is only available in the UK on prescription as an anti-depressant called Optimax by Merck. It was banned for over-the-counter sale following a contaminated batch produced by a Japanese manufacturer who had developed a method of production involving genetically modifying an organism to produce tryptophan. This resulted in a contamination that caused a disease outbreak called eosinophilia myalgia syndrome. This proved fatal for a number of people and was the first major blunder of genetic engineering.


While tryptophan itself is both safe and effective it is no longer available over the counter in the UK. Since it competes for absorption with other amino acids and its absorption is assisted by ingesting carbohydrate which helps carry tryptophan from the blood into the brain. Hence, it is best to supplement tryptophan with a fruit snack, away from other protein foods.




5-HTP - The Best Natural Anti-depressant


More effective and available than tryptophan is 5-HTP ( 5–hydroxytryptophan), which is a more biologically active form of tryptophan. While 5-HTP is not a direct precursor for DMT, it is the most effective precursor for serotonin. By providing the brain with the raw material to make serotonin this spares tryptophan for producing other important tryptamines, such as DMT.


5-HTP is ten times more powerful than tryptophan hence the dose needed for a psychoactive effect is a tenth. Like tryptophan it has proven to be a very effective anti-depressant, at least as effective as the best anti-depressant drugs without the same high risk of side-effects (see chapter 7). 5-HTP occurs naturally in an African plant called the Griffonia simplifica and is available as a nutritional supplement.


The dosage of 5-HTP that has been used in the treatment of depression is 200mg to 300mg a day. 5-HTP doesn’t compete for absorption with other amino acids and is therefore well absorbed both with food and without. The amount needed to promote a sense of connection is 100mg a day, or less if taken in combination with other ‘connecting’ nutrients.


A word of caution: More is not better. Serotonin overload can cause symptoms of tremor, nausea, vomiting, elevated temperature, abnormal heart beat and, in extreme cases, coma, leading to death. It occurs within 2 hours and symptoms may subside within 6 to 24 hours. This does not occur with either tryptophan or 5-HTP in the dose ranges we recommend. However, we do not recommend simultaneously supplementing these nutrients with anti-depressant drugs which effectively keep more serotonin in circulation by stopping its breakdown unless under medical guidance, nor do we recommend combining these nutrients with entheogens which temporarily raise serotonin levels.




S-Adenosyl Methionine (SAM) – The Master Tuner


SAMe is the master tuner as far as the chemistry of connection is concerned. It donates ‘methyl’ groups and helps to make naturally occurring tryptamines that are part of the brain’s well-tuned chemistry. The methylation of tryptamine, for example, results in DMT. The body can and does make SAMe from the constituent of protein, methionine. Having enough vitamin B6, B12 and folic acid helps the body maximise its production of SAMe.


SAMe also helps neurotransmitters deliver their messages to the receptor sites by sharpening up their activity. By methylating phospholipids, from which nerve cell membranes are made, SAMe improves cellular communication between nerve cells.


SAMe can also help you get a good night's sleep and promotes dreaming. This is because the brain’s manufacture of melatonin, a key neurotransmitter for sleep and dreaming, depends on SAMe. Melatonin is made from serotonin, however the conversion depends upon SAMe.


SAMe has been well proven as an anti-depressant, however its use tends to also enhance a feeling of well-being and connection in those who are not depressed. While a positive response is often felt within a week, and often within days, it may take as long as 4 weeks. In general, the longer SAMe is used, the more beneficial the results.


SAMe should be taken on an empty stomach, preferably 1 hour away from food, starting at a dosage of 200mg twice daily. If results aren’t seen in a few days, the dose can be increased gradually, up to the maximum dose of 400mg four times daily, if needed. Most often, 400mg per day is sufficient. SAMe should also be taken with its cofactors, Vitamin B6 (100 mg), Vitamin B12 (100 mcg) and Folic acid (1000 mcg). It is safe to use during pregnancy and nursing.


Unfortunately, SAMe is currently both expensive and relatively unstable as a supplement. SAMe also becomes unstable at higher temperatures and should be kept refrigerated whenever possible. Pharmaceutical-grade SAMe comes in two forms, tosylate and a newer, more stable form called butanedisulfonate. The former quickly degrades upon exposure to heat and/or moisture and if improperly handled during manufacture, can be worthless. Both forms are relatively stable in enteric coated tablets. In comparing products, potency, and price, look for the amount of active ingredient on the label. For example, 200 mg of s-adenosyl-methionine butanedisulfonate provides only 50% or 100 mg of SAMe. Purchase from a reputable company, not a one newly on the SAMe bandwagon.


Enteric coated tablets are much better becaue they ensure stability and reduce the chances of a sometimes reported side effect of nausea and gastrointestinal disturbances. Reducing the dose size and taking it with meals usually overcomes this potential problem, although the food will reduce its potency somewhat.


A word of caution: Although not reported in the literature, higher doses may lead to irritability and anxiety. If this continues even on the lowest dose, the product should be discontinued. There are no reported negative interactions with other medications or nutritional supplements.




Trimethylglycine (TMG) - The Alternative to SAMe


Until stable SAMe supplements become widely available your best bet is to supplement trimethylglycine (TMG). The body can make SAMe directly from TMG, which is both stable and much less expensive. While it has not been so extensively researched as SAMe the fact that it is a direct precursor of SAMe would predict that its effect would be very similar although you need more. Also, TMG helps the body to make more SAMe from dietary protein. TMG is extracted from sugar beets and is also found in broccoli and spinach. It has no reported of side effects other than brief muscle tension headaches if it is taken in very large quantities without food. Optimal doses needed to raise SAMe levels in the body are 1,000 - 3000 mg per day. In combined formulas, a 500mg dose is sufficient.




B3, B6, B12 and Folic Acid – Your Brain’s Best Friends


If SAM is the source of the methyl groups that transform one brain chemical into another, B vitamins are the delivery boys who can accept or donate methyl (carbon based molecules) groups. They are the real workers in the enzymes that turn one brain chemical into another and keep you feeling connected.


For some enzymes you need vitamin B3, for other B6, B12 or folic acid. Not surprisingly, deficiency of any one of these leads to dis-connection and is associated with depression, mental illness, schizophrenia and unpleasant hallucinations. Supplementing these has the reverse effect and has been shown to dramatically improve a person’s mental and emotional well-being.


As long ago as 1957 Drs Humphrey Osmond and Abram Hoffer from Saskatchewan in Canada, proved that supplementing niacin normalised behaviour in those diagnosed with schizophrenia in the first ever double-blind study in the history of psychiatry. Dr Abram Hoffer, now in his 80’s has treated over 5,000 patients with schizophrenia and claims an 80 per cent success rate using B3 and other ‘connector-nutrients’. His definition of cure – free of symptoms, able to socialise and paying income tax! Hoffer and Osmond were among the first scientists to investigate the chemistry of entheogens and, from this, developed their theories on how to treat the mentally ill suffering from unpleasant hallucinations. Their theories have proven correct and, to this day Hoffer believes an optimal intake of these nutrients is essential to be naturally high. (Osmond introduced Aldous Huxley to mescaline, the entheogen found in the peyote cactus. To describe his experience he wrote The Doors of Perception, from which Jim Morrison named his band, the Doors – an interesting connection.)


Meanwhile, Dr Carl Pfeiffer at the Brain Bio Center in Princeton had also been investigating the chemistry of the brain in relation to mental health and illness. He discovered that deficiency in vitamin B6 (pyridoxine) and zinc (pyridoxine is ‘activated’ in the body by a zinc-dependent enzyme) also created dis-connection, diagnosed as mental illness. Supplementing vitamin B6 and zinc corrected this abnormal chemistry and improved their mental health and experience of connection. B6 is now known to help SAMe donate its methyl groups in the chemistry of connection.


Folic acid is also a methyl donor. Research at Kings College Hospital and the Institute of Psychiatry in London found that one third of all patients with either severe depression of schizophrenia were deficient in folic acid Supplementing folic acid for six months made a big difference in their symptoms and ability to relate. Folic acid, together with vitamin B12, is needed to turn the amino acids tryptophan into serotonin and tyrosine into dopamine. Without these vitamins the higher brain centres simply can’t work properly.


Of course, the effect of these nutrients in isolation is not nearly as powerful as the nutrients in combination and consequently, to enhance connection it is best to supplement the following levels every day:


Niacin (B3) 100mg

Pyridoxine (B6) 50mg

Cyanocobalamine (B12) 50mcg

Folic acid 500mcg

Plus the minerals…

Zinc 15mg

Manganese 5mg

Magnesium 350mg


Niacin comes in two forms – niacin and niacinamide. Niacin, at dosages above 50mg, makes you blush. This vasodilatory effect is beneficial in many ways, however is not to everybody’s choosing. To avoid the flushing effect supplement no more than 50mg of niacin, and the rest in the form of niacinamide.

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