Serotonin-antimetabolite theory of LSD intoxication

In 1954, Gaddum and colleagues suggested that 5-HT interactions might be implicated in the hallucinogen mechanism of action. Similar ideas were being developed simultaneously on the other side of the Atlantic by Woolley and Shaw (A. R. Green, 2008), who advanced the "5-HT antimetabolite" theory of LSD intoxication, stating,

"It is the lack of serotonin which is the cause of the disorder." (D. W. Woolley, 1954)

This hypothesis has influenced LSD researchers everywhere and the topic is still being hashed out; even in 2008, there were 2 reviews on "LSD and 5-HT". The 5-HT antimetabolite hypothesis has been disproved to the most part, though it still gains in popularity by conforming with the contemporary preoccupation with serotonin amongst neurophysiologists and behavioral scientists.

Though there is some chemical resemblance between 5-HT and LSD, they are two very different molecules that differ by multiple atoms. It is very unfortunate that the resemblance between 5-HT and LSD has side-tracked researchers from focusing on something far more interesting -- that there are some single-atom alterations to the structure of LSD, such as bromine in the 2-position (BOL-148), that yield drugs that are completely ineffective compared to LSD!

"One atom of hydrogen more, one less of carbon, changes an uninteresting substance into a pigment or even an explosive." (A. Schoenberg)

The important field of structure-activity relationships in LSD and its derivatives has been strangely neglected while researchers have looked into correlations between LSD and 5-HT. The research program should have included the synthesis of a number of analogs of LSD according to systematic principles to determine the role of the details in its molecular structure play in the mode of action on the psyche (J. Smythies). Studies into LSD analogs, especially human studies of the Shulgin type, are rare in the literature. They are far fewer in number than studies that have compared the actions of LSD with 5-HT.

One strike against the 5-HT-antimetabolite LSD hypothesis is the fact that a number of derivatives of LSD-25 are more potent antagonists of 5-HT peripherally but lack psychotomimetic activity. MLD-41 and UML-491 are classic examples of LSD derivatives with exceptional anti-5-HT activity, but that are inactive at LSD dose levels.

Table 1 (below) lists different LSD derivatives. The first column indicates the LSD-like activity in humans, as assessed with Abramson's Cold Spring Harbor questionnaire, and the second column indicates anti-5-HT activity in the rat uterus preparation as reported by Cerletti and coworkers.

From 5-HT pain

No clear correlation was found between the effective dose of a hallucinogenic drug and its potency in blocking the action of 5-HT on isolated smooth muscle preparations (H. H. Gettner, 1965). For example, MLD-41 and UML-491 had far greater anti-5-HT ability (370 and 400) than LSD (100) and had activities in humans that are rated at 36 and 0.66 as compared to LSD at 100.

BOL-148 has about the same anti-5-HT ability as LSD, and its activity is 7.2 as compared to LSD at 100. Rothlin said,

". . . it is difficult to admit a correlation of the psychic effects induced by LSD and its anti-5-HT property, since 2-brom-LSD possesses the same anti-5-HT activity in vitro and in vivo, but it lacks the psychotogenic action." (E. Rothlin, 1957)

One of the barriers for studying 5-HT is the lack of absorption of 5-HT when it is delivered intravenously, since 5-HT doesn't cross the blood-brain barrier. This problem can be circumvented if 5-HT is delivered straight to the ventricles of cat brain. If LSD intoxication were due to a lack of 5-HT, then a reversal of LSD cat behavior would be expected when 5-HT is delivered intraventricularly to brain. This experiment was performed by Schwarz and colleagues, in 1956, who found no change in cat behavior when 5-HT was administered intraventricularly, at a time period after mescaline or LSD (B. E. Schwarz, 1956).

Opposite the 5-HT-antimetabolite theory is the hypothesis that the effects of LSD are due to an increase of 5-HT levels. This hypothesis does not account for early findings by Gaddum and Cerletti that LSD hardly ever potentiates the effect of 5-HT, and is generally not well-supported. An excess 5-HT alone does not produce hallucinogenic behavior, since carcinoid tumor patients, who exhibit some of the highest known concentrations of 5-HT in nature, tend to complain more of diarrhea and abdominal cramps than psychotic thinking. In addition, it was found that the psychotomimetic effects of LSD were not prevented by the hyperserotonemia present in carcinoid patients (R. Schneckloth, 1957). Further, the effects of LSD are probably unrelated to an enhancement of 5-HT levels, since treatments that elevate 5-HT itself, such as monoamine oxidase inhibitors or selective serotonin uptake blockers, are not hallucinogenic and may in fact, attenuate the subjective effects of hallucinogens in humans (G. K. Aghajanian, 1999).
 

The relationship between LSD and 5-HT is complex. LSD is one of the most specific serotonin inhibitors within a large group of several amide derivatives of lysergic acid, and MLD-41 and UML-491 together with LSD are amongst the most powerful anti-serotonin drugs studied in the model of 5-HT edema, yet, hallucinogen drug potency is not predicted by these measures. Quantum chemical parameters of a drug, such as its ionization potential energy or HOMO energy, are the most robust predictor of hallucinogen drug potency.

References

SCHWARZ B. E., K. G. WAKIM, R. G. BICKFORD and F. R. LICHTENHELD 1956. Behavioral and electroencephalographic effects of hallucinogenic drugs; changes in cats on intraventricular injection. A. M. A. Archives of neurology and psychiatry, 75, 83-90.

SCHNECKLOTH R., I. H. PAGE, F. D. GRECO and A. C. CORCORAN 1957. Effects of serotonin antagonists in normal subjects and patients with carcinoid tumors. Circulation, 16, 523-532.

Gettner H. H., A. Rolo and H. A. Abramson 1965. Lysergic acid diethylamide (LSD 25). 36. Comparison of effect of methysergide (UML 491) on goldfish and Siamese fighting fish. The Journal of psychology, 61, 87-92.

Aghajanian G. K. and G. J. Marek 1999. Serotonin and hallucinogens. Neuropsychopharmacology, 21, 16S-23S.

Green A. R. 2008. Gaddum and LSD: the birth and growth of experimental and clinical neuropharmacology research on 5-HT in the UK. British journal of pharmacology, 154, 1583-1599.

Cerletti 1958

Normally, 5-HT causes smooth muscle to contract, either by a direct action on the muscle fibers or through excitation of the network of nerves within the muscle. In the original work by Gaddum et al in 1953, small amounts of LSD (0.6 ug/L) inhibited the contraction of rat uterine muscle due to 15 ug/L 5-HT, suggesting the LSD specifically blocks the response of smooth muscle to 5-HT (J. H. Gaddum, 1953).

In 1954, Gaddum found that LSD was the most active and specific drug to block 5-HT-constriction of muscle; LSD was the most active drug in a series of methylindoles, aminoindoles, and substituted tryptamines. A concentration of LSD reduced the effect of 5-HT so that after 10 minutes, the dose of 5-HT had to be doubled to reproduce the original effect (J. H. Gaddum, 1954).

This finding is illustrated by the figure below. As shown, 20 and 24 ng of 5-HT lead to 2 prominent spikes in the graph at time 0 and time 4; this activity represents the constriction of muscle. At time 8, 8 ng of 5-HT caused half the maximum effect. Then, LSD (1 ug/L) was added to the bath at time 9 minutes, and a double dose of 5-HT (16 ng) was applied at intervals. The time at which the effect of this double dose was equal to the original effect of the single dose was between 16 and 20 minutes, or 9 minutes after the addition of the antagonist, suggesting that LSD specifically blocks the response of smooth muscle to 5-HT.

From 5-HT pain

Following these initial demonstrations, Cerletti and colleagues undertook an investigation of the 5-HT blocking ability of LSD and 40 analogs of LSD, in 1958. This study was quite unique because of the number of LSD analogs tested. Similar to previous studies, strips of muscle were cut from a rat uterus, and bathed in a solution containing drugs. Muscle contractions were recorded with a lever on a smoked drum. Each compound was tested in at least 8 experiments.

Figure 1 (below) shows a typical example of effects obtained with increasing doses of LSD. The serotonin (S) dose (10 ng) is unchanged throughout the experiment. Note that LSD caused a blocking of muscle constriction in response to the serotonin (S) dose.

From 5-HT pain

One of the most potent anti-5-HT agents was found to be MLD-41, an LSD analog with a methyl group at position-1. The figure below shows a comparison of 5-HT inhibition on rat uterus by LSD (left) and MLD-41 (right). A stronger and longer lasting effect was produced by one half the dose of MLD-41 (2E-9 M) as compared with LSD (4E-9 M).

From 5-HT pain

Its remarkable that these investigators tested over 40 unique LSD analogs, which are rather difficult to synthesize. The results of their studies provide an abundance of information about structure-activity relationships. For example, studies of the 4 isomers of LSD (d-LSD, l-LSD, d-iso-LSD, and l-iso-LSD) revealed the specificity of the d-stereoisomer of LSD for eliciting biological effects. Cerletti wrote,

"According to the molecular structure of lysergic acid, four isomers of LSD are possible. All four have been synthetized and tested . . . the diethylamide of l-lysergic acid as well as the analogous derivatives of d- and l-isolysergic acid are practically ineffective, being about one thousand times weaker than LSD-25." (A. Cerletti, 1958) 

The researchers also studied d-Dihydro-LSD, which has a double bond between carbon 9 and carbon 10, and d-Lumi-LSD, which does not. Saturation of the 9,10 double bond (in d-Lumi-LSD) was accomplished by addition of one molecule of water under the influence of light. Cerletti wrote,

"By hydrogenation of the double bond between the carbon atoms 9 and 10, LSD loses about half of its antiserotonin activity." (A. Cerletti, 1958)

Another LSD analog studied was 1-acetyl-LSD, which was about twice as potent as LSD having anti-serotonin activity. The compound with the most potent antiserotonin activity was 1-methyl-2-Bromo lysergic acid diethylamide, which has combined substitution of a methyl group and a bromine atom in positions 1 and 2, respectively. 

Cerletti and colleagues also compared the 5-HT-blocking ability of LSD versus natural ergot alkaloids. They included in their study a large group of peptide alkaloids of ergot and their hydrogenated derivatives. Results showed that methylergonovine was quite effective and specific at inhibiting 5-HT.

The initial discovery that LSD is a potent antagonist of 5-HT in isolated smooth muscle preparations became a platform of the theory that LSD's mental effects may be related to blocking serotonin. However, Gettner later showed, in 1965, that there is no clear correlation between the effective human dose of a hallucinogenic drug and its potency in blocking the action of 5-HT on isolated smooth muscle preparations.

It is important to recognize that LSD hardly ever, rarely, potentiates the effect of 5-HT, as shown by Gaddum and Cerletti's work.

Few other researchers have had the opportunity to test biological activity in 40 unique LSD analogs. Cerletti wrote,

". . .the fact remains that LSD is the most active and also the most specific serotonin inhibitor within a large group of several amide derivatives of lysergic acid." (A. Cerletti, 1958)

Although it might seem that studies carried out on a slice of muscle bathed in solution are highly reduced, this preparation is sensitive to very low concentrations of drug, and can be extremely useful to pharmacologists.

Reference

GADDUM J. H. 1953. Antagonism between lysergic acid diethylamide and 5-hydroxytryptamine. The Journal of Physiology, 121, 15P.

GADDUM J. H. and K. A. HAMEED 1954. Drugs which antagonize 5-hydroxytryptamine. British Journal of Pharmacology and Chemotherapy, 9, 240-248.

CERLETTI A. and W. DOEPFNER 1958. Comparative study on the serotonin antagonism of amide derivatives of lysergic acid and of ergot alkaloids. The Journal of Pharmacology and Experimental Therapeutics, 122, 124-136.

Periodic table of the elements

From Hecht, Selig

The atom is the smallest particle that makes up that type of material called an element. The element retains in characteristics when subdivided into atoms. More than 100 elements have been identified. They can be arranged into a table of increasing weight, and can be grouped into families of material having similar properties. This arrangement is called the periodic table of the elements.

The periodic table of the elements is an orderly arrangement of the elements in ascending atomic number (number of planetary electrons) and also in atomic weight (number of protons and neutrons in the nucleus). The various kinds of atoms have distinct masses or weights with respect to each other. The element most closely approaching unity (meaning 1) is hydrogen whose atomic weight is 1.008. The pretty ribbon view of the periodic table of elements (figure above), shows hydrogen on both ribbons.

"At present some 112 chemical elements have been identified. A few have been known since before recorded history, principally because they occur in nature as elements rather than in combination with one another in compounds. Gold, silver, lead, copper, and sulfur are chief among them. Gold is found in streams in the form of little granules (placer gold) or nuggets in loosely consolidated rock. Sulfur is associated with volcanoes, and copper can often be found in its native state in shallow mines. Iron occurs in its elemental state only rarely (in meteorites). Usually it is combined with oxygen or other elements. In the second millennium B.C., ancient metallurgists somehow learned to reduce iron oxide to iron with charcoal in forced-draft fires, and the Iron Age was inaugurated.

The names of the chemical elements and the symbols that designate them are fascinating subjects. Many have Latin roots, such as gold (aurum, symbol Au), copper (cuprum, Cu), iron (ferrum, Fe) and mercury (hydrargyrum, Hg). Hydrogen (H) means "water former." Potassium (kalium, K) takes its common name from potash (potassium carbonate), a useful chemical obtained in early times by leaching the ashes of wood fires with water. Many elements take their names from Greek and Roman mythology: cerium (Ce) from Ceres, goddess of plenty; tantalum (Ta) from Tantalus; niobium (Nb) from Niobe, daughter of Tantalus. Some elements are named for continents: europium (Eu), americium (Am). Others are named after countries: germanium (Ge), francium (Fr), polonium (Po). Cities provide the names of others: holmium (Stockholm, Ho), ytterbium (Ytterby, Yb), berkelium (Berkeley, Bk). Some are named for the planets: uranium (U), plutonium (Pu), neptunium (Np). Others take their names from colors: praseodymium (green, Pr), rubium (red, Rb), cesium (sky blue, Cs). Still others honor great scientists: curium (Marie Curie, Cm), mendelevium (Dmitri Mendeleev, Md), fermium (Enrico Fermi, Fm), einsteinium (Albert Einstein, Es), seaborgium (Glenn Seaborg, Sg)."  (D. W. Oxtoby, 1999)

Reference

Hecht S. Explaining the atom. The Viking Press: New York, 1964.

Oxtoby D. W., H. P. Gillis and N. H. Nachtrieb. Principles of modern chemistry. Saunders College Publishing: Fort Worth, Texas, 1999.

Karreman 1959

In a classic paper by Karreman and Szent-Gyorgyi in 1959, the authors propose that a charge-transfer reaction may be a prominent factor in the mental changes caused by certain drug molecules. Karreman and Szent-Gyorgyi reported, for the first time, a negative K value for the highest occupied molecular orbital (HOMO) of chlorpromazine, implying particularly good electron-donor properties for this mind-affecting drug.

"Chlorpromazine is the first substance ever found in which, in its ordinary stable state, the highest filled level corresponds to an antibonding orbital, as indicated by the minus sign of K. This makes chlorpromazine a quite extraordinary strong electron donor." (G. Karreman, 1959)

The reported K value=-0.217 for the highest filled orbital of chlorpromazine, was somewhat unexpected since it meant that the HOMO of chlorpromazine would be classified as an anti-bonding orbital. True to the O in its name, the HOMO is usually "occupied"; typically one or two electrons occupy the HOMO. In comparison, anti-bonding orbitals are usually unoccupied; anti-bonding orbitals typically contain zero electrons in the ground state. How could it be that the HOMO would have properties of an anti-bonding orbital?

Anti-bonding orbitals do form bonds with other orbitals, that are as stable as typical bonds formed by bonding molecular orbitals, and in this regard the term "anti-bonding" orbital is unfortunate. But obviously anti-bonding orbitals wouldn't be named as such if they were usually occupied by electrons.

In addition to their work on chlorpromazine, Karreman and Szent-Gyorgyi performed Huckel calculations on LSD, serotonin, and DMT. They obtained a small positive value of K=0.218 for the HOMO of LSD, and concluded that LSD should be a very good electron donor based on this value. Based on their calculations, Karreman and colleagues suggested that psychoactive drugs like serotonin, DMT, LSD, and chlorpromazine may function as electron donors.

What is the significance of a HOMO orbital with a negative K value?

The Pullmans had recently shown a negative K value of the HOMO in reduced FMNH2, a riboflavin coenzyme (Table 1, below). According to these authors, the reduced form of FMNH2 possessed a very unusual characteristic, which had not been observed previously in any other existing compound, namely that its HOMO was not only a very high-lying one but an anti-bonding one, of the type of orbital which is generally occupied by electrons only in the excited states of molecules. This represents a fundamentally unstable arrangement and suggests that reduced FMNH2 has an exceptionally strong natural tendency to expel the electrons located at its HOMO. Experimental observation confirms that FMNH2 in the reduced form tends to give up electrons, and this property accounts for its outstanding electron donor properties and autooxidizability.

Table 1 (below) shows HOMO and LEMO values for protonated and unprotonated methylene blue (MeB), DPN, and FMN. MeBH (K=-0.232) and FMNH2 (K=-0.105) are the only 2 compounds in this table with a negative K HOMO value, and these 2 compounds are distinguished from the other compounds by their unusual electron-donating ability.

From Hallucinogens HOMO, charge-transfer

Negative values for highest orbitals are usual only for orbitals occupied in the excited states of molecules. The calculations suggest that the ground state of certain chemical substances, such as FMNH2, methylene blue, and chlorpromazine, mimics the configuration of an excited state molecule. This property should be associated with an unusually low ionization potential energy and extremely pronounced electron donor capacities. 

While a negative K value of the HOMO was not found for the LSD molecule, its K value was small, implying pronounced electron donating ability.

What is the normal relationship of an anti-bonding orbital to the ground state, and what is the "ground state"?

 

In the ground state molecule, all electrons have coalesced into a single piece of matter. The ground state is comprised of certain energy levels, that are occupied by the completed set of electrons. Pairs of electrons fill the bonding orbitals, and the anti-bonding orbitals are usually empty. High-lying orbitals such as the HOMO have the ability to accommodate 1-2 electrons, these electrons are susceptible to being ejected from the molecule, aka ionized, if and when stimulus energy hits a molecule. An ionized electron is less attached to the molecule; sometimes it is said to be free. This can be achieved with an input of a definite amount of energy hv. It is said that the energy hv promotes the electron from a bonding to an anti-bonding orbital. The anti-bonding orbital is a construction of the mind, it represents a space that is somehow attached to the molecule, but for all purposes, it is never actually occupied by electrons in the molecule's ground state configuration. The process is reversible. Movement of the electron from the anti-bonding to bonding orbital results in an emission of the energy hv, with a certain color or certain definite frequency. 

The ground state of most molecules is described as having electrons in bonding orbitals only. Yet with chlorpromazine, FMNH2, and methylene blue, we encounter the unique situation where the HOMO is an anti-bonding orbital. We expect a spontaneous expulsion of the high-lying electron at this orbital, in the same way that it is expected that electrons generally move from anti-bonding to bonding orbitals.

Its unexpected to discuss the excited state, and the ground state, at the same time, but the ground state of chlorpromazine is reported to have 1-2 electrons in an anti-bonding configuration. Typically, for electrons to occupy the anti-bonding orbitals, energy must be put into the molecule in the form of light. But presumably in the case of some biologically active molecules like chlorpromazine or FMNH2, an electron populates the HOMO, readying the compound to be able to exchange electrons while in the ground state.

Most descriptions of matter are descriptions of matter in the ground state, containing electron pairs. These descriptions are sufficient as long as the molecule is kept away from light or heat energy, which perturb its ground state. But in reality, electron pairs in matter are constantly interacting with single electrons or photons. Energy is transferred from matter to field and back again. Though we have the concept of a "united molecule" and ground state energy level diagrams to describe matter, the field in which these electrons are radiated or absorbed is rarely talked about. Presumably the field has no place in the matter. Its just there to absorb or radiate photons when the matter is ready to take them or give them up. The embeddedness of the field within matter was revealed when Huckel calculations showed that an anti-bonding orbital may be considered as part of the ground state of chlorpromazine. With this discovery, the distinction between ground and excited states becomes less clear. Certain organic molecules are prepared to "do work" and exchange electrons in the ground state.

There is no reason to doubt the calculations. Huckel analysis gave evidence of a very labile electron occupying the chlorpromazine HOMO and described it in further terms as an excellent electron donor. Naturally the authors who discovered this presumed that this physical property could be related with the mind-altering ability of the drug chlorpromazine.

Concept of free radicals, after 1959
 

The existence of stable free radicals, such as FMNH2 and chlorpromazine, has since been confirmed. Whereas most molecules pass through an odd-electron configuration on the transition state to another molecule and then settle back down to an even-electron configuration, there are certain molecules whose ground state is more favorable to the existence of odd-electrons, and these are called "stable" radical molecules. 

The reduced form of FMNH2 is a familiar example, but there are many small molecules that form stable radicals. The oxidation of phenol can lead to the final formation of quinoid structures, a system where the delocalization of the unpaired electron is developed very strongly. Quinoid radicals have considerably greater stability than the phenol radicals that formed them. Another example is Wurster's blue cation radical, which is stable even at room temperature. Its stability is ascribed to electron delocalization in its semiquinone structure. Indole and tryptophan are considered to be stable radical molecules. Another stable radical is melanin, which has an ESR spectra that resists 24 h of refluxing in hydrochloric acid. The planar molecule anthracene has a radical state at room temperature. Diphenylpicrylhydrazyl (DPPH) is a free radical that is often used as an ESR standard. Nitric oxide, chlorine dioxide, and alkali superoxides are examples of stable inorganic free radicals.

The existence of radicals in the ground state has been more or less proven since Karreman and Szent-Gyorgyi's paper on chlorpromazine and LSD. These molecules seem to serve as miniature case studies of what is life itself, in terms of what it takes (number of atoms, types of atoms, their connectivity) to harbor a little electron well in a little piece of matter, which will be able to exchange electrons in the ground state. This ushers in a new era where energy is not bounding and rebounding off of everything. In addition to the world in which there is an equal and opposite reaction for every action, there is a world of electron wells. No action required to reach the action state.

Reference

Ingram D. J. E. Free radicals as studied by electron spin resonance. Butterworths Scientific Publications: London, 1958.

KARREMAN G., I. ISENBERG and A. SZENT-GYORGYI (1959). On the mechanism of action of chlorpromazine. Science, 130, 1191-1192. doi:10.1126/science.130.3383.1191

PULLMAN B. and A. PULLMAN (1959). The oxido-reductive properties of organic dyes of biological importance. Biochimica et Biophysica Acta, 35, 535-537.

ORLOFF M. K. and D. D. FITTS (1961). Molecular-orbital treatment of phenothiazine and some related molecules. Biochimica et Biophysica Acta, 47, 596-599.

Kier L. B. Molecular orbital theory in drug research. De Stevens, G., Ed.; Academic press: New York, 1971.

Bock H., K. Gharagozloo-Hubmann, M. Sievert, T. Prisner and Z. Havlas (2000). Single crystals of an ionic anthracene aggregate with a triplet ground state. Nature, 404, 267-269.

Domelsmith 1, what is the ionization potential?

Photoelectron spectroscopy has been used to study the electron-donating ability of hallucinogenic drugs. My Domelsmith series 1-8 covers the ionization potentials of LSD, and some tryptamines, phenothiazines, amphetamines, and betacarbolines. LSD, DMT, and some phenothiazine drugs have an abnormally low energy ionization potential, of approximately 7 electron volts (eV). This fact is not interesting simply unto itself, for what it may reveal about the physical chemistry of these molecules. The ionization potential energies of LSD and related drugs are found to be significantly correlated with the ability to displace LSD binding from rat brain membranes and with drug potency to block avoidance response behavior in rats. These studies show a role of charge-transfer mechanisms in consciousness alteration.

What is the ionization potential?

The first ionization energy is the energy it takes to remove one electron from a neutral atom in the gas phase, thus the technique of photoelectron spectroscopy requires the sample to be vaporized first. The sample gas is irradiated with an incident beam of photons from a Helium lamp. The energy required to remove the outermost electrons from the molecule is the ionization energy, calculated as the difference between the photon energy of the Helium source, and the energy of the ejected electron. The amount of energy that is required to remove the outermost electrons from free atoms and molecules is on the order of approximately 10 electron volts (D. E. Ingram, 1958).

The photoelectron spectrum of a molecule contains a series of peaks, each corresponding to a molecular orbital energy level. Photoelectron spectras of 4 halogen gases are shown in the figure below. Ionization potential energy (X-axis) ranges from 15.5-16.5 eV in fluorine (F2), 12-13 eV in chlorine (Cl2), 10.5-11 eV in bromine (Br2) and 9-10.5 eV in iodine (I2).

From Domelsmith ionization potential

Of the 4 halogen gases shown, iodine has the smallest ionization potential energy (~9.5 eV). It would require approximately 9.5 eV of energy to remove the outermost electrons from the orbitals of iodine gas. The technique of photoelectron spectroscopy can be used to assess the relative reactivity of halogens. In this case, iodine is the most reactive gas, because it requires the least amount of energy to perturb its structure. Fluorine, chlorine, and bromine are relatively more stable than iodine.

Possibly the most direct evidence that we have for the existence of molecular orbitals comes from photoelectron spectroscopy. It is customary to regard the photoelectron spectrum as a direct representation of the molecular orbital energy diagram. Each peak in the photoelectron spectra is assigned to the energy of a particular molecular orbital.

It is useful to know the amount of energy required to remove an electron from the outermost orbitals of a molecule, because the chemical reactivity of some reactions is dependent upon the ionization potentials of the reagents. Indeed, the ionization potential energy measured with photoelectron spectroscopy has been an important empirical parameter for determining chemical reactivity. For example in the Diels-Alder reaction, the rate of formation of a cycloaddition product depends on the ionization potential of the diene. In the example of alkene bromination, as shown in Figure 3 below, there is a linear plot between the alkene ionization potential energy (IP) and the log of the rate constants (log Krel). Those alkenes with the lowest ionization potential react fastest with bromine and vice versa.

From Domelsmith ionization potential

What is the relationship of ionization potential energy to HOMO energy?

It has been shown that the ionization potential energy is closely related to the HOMO energy of a molecule. There is very good agreement between the ionization potential energies that are measured in a photoelectron spectrometer, and the HOMO values of molecular orbitals that are obtained by theoretical calculations. The graph below shows a correlation between the ionization potential energy and Ehomo for some tryptamines and phenethylamines.

From Domelsmith ionization potential

Koopman's theory states that the physical property of a molecule which correlates most closely with its ionization potential is the HOMO energy. The figure below shows a reasonably linear relationship between ionization potential energy and EHOMO.

From Domelsmith ionization potential

In practice, the ionization potential energy of a molecule refers to a quantity that has been measured with the use of a photoelectron spectrometer, while the HOMO energy of a molecule refers to a quantity that is arrived at by theoretical calculations. Either the HOMO energy or the ionization potential energy of a molecule can be used to predict its chemical reactivity. It is significant that correlations have been found between the hallucinogenic dose of a drug with its HOMO energy, or with its ionization potential energy, although obviously if one type of correlation is found, the other would be expected based on Koopman's theory.

What more can be said about the "outermost" electron which is displaced by the photoelectron spectrometer?

The electron or electron pair occupying the HOMO is subject to the least attraction to the core; this high-lying single or pair is "on the frontier" of the energy levels. HOMO and other high-lying orbitals have properties that are different from inner shell orbitals, such as s orbitals. The ionization of HOMO electrons requires less energy than inner shells, and the HOMO electron or electrons are more delocalized in space. Generally speaking, there has to be a gap or a space, between the closed-shell orbital configurations of a molecule, which gives it its identity, and the alien stuff "out there". Delocalized electrons in HOMOs represent this space, and most chemistry takes place here.

In the study of psychoactive tryptamines and amphetamines, and LSD, the high-lying delocalized electrons in the HOMO are found in the "pi systems", which are hybridized p orbitals belonging to the carbon and nitrogen atoms that make up these molecules.

Reference

Kier L. B. Molecular orbital theory in drug research. Academic press: New York, 1971.

Domelsmith L. N., L. L. Munchausen and K. N. Houk (1977). Photoelectron spectra of psychotropic drugs. 1. Phenethylamines, tryptamines, and LSD Journal of the American Chemical Society, 99, 4311-4321.

Domelsmith L. N. and K. N. Houk (1978). Photoelectron spectroscopic studies of hallucinogens: the use of ionization potentials in QSAR. NIDA Research monograph, 22, 423-440.

Who was Dr. Harold A. Abramson?

H. A. Abramson was one of the most prevalent LSD researchers of the 20th century.

From LSD fish

Abramson spent his life as a clinical allergist, and he had an intense interest in the actions of LSD. He did studies involving human subjects, LSD, and psilocybin, and he pioneered the LSD fish surfacing reaction. He was involved in research with LSD analogs including methysergide and BOL-148, and cross-tolerance between LSD and these drugs in human subjects. He wrote a series of 40 papers about "Lysergic acid diethylamide."

At a conference on LSD in 1959, Abramson said,

"If I were to say what LSD does, I would refer to experimental work I have done on the Siamese fighting fish, where 1 ug/kg of potassium cyanide (a cytochrome oxidase inhibitor) and sodium azide and LSD will act in very much the same fashion: The fish will be in a nose-up, tail-down stupor, lasting for days in the case of sodium azide, and for a shorter period in the case of potassium cyanide, because it is more rapidly oxidized. We can produce the same effect with hypoxia." (H.A. Abramson, 1959)

Early in his career, Abramson acquired skills in basic immunology, human physiology and pharmacology. He spoke about his transition to LSD from private practice at a conference in 1959.

"About 30 years ago, Dr. Fremont-Smith and I were tutors together at Harvard in the Division of Biochemical Sciences. My main interests originally were physical chemistry and immunology. About 1935, I began the private practice of medicine in New York. Though I had been teaching immunology, I found that conventional treatment yielded very poor results in the many cases of eczema and asthma which I met in practice. It was Dr. Fremont-Smith, by this time in New York, who made me realize that I knew a lot about allergy, but very little about patients. In going over my cases with him, I learned how to appraise an illness, not only in terms of the organic factors, but from the standpoint of the individual as a whole. Soon, I was practicing some psychiatry under his guidance. Realizing that my interests lay in psychiatry and psychotherapy, I proceeded to get training in these areas. But one of my difficulties was being unable to bring the laboratory into the area of psychiatry in the way in which I had been accustomed. I had been working with mathematics and surface chemistry and was really very concerned about the lack of contact between psychiatry, as I knew it then, and the laboratory. Then I saw some papers on LSD. These studies seemed to me to bring the laboratory and psychiatry together. I began to work with LSD in 1951, work which has given me great satisfaction, because it involves my interests in psychoanalysis, psychotherapy, enzyme reactions, and surface chemistry, as well as biochemistry and pharmacology." (H.A. Abramson, 1959)

Abramson frequently wrote about the usefulness of LSD to treat "allergic" phenomena.

"... the use of methysergide and LSD in the treatment of migraine and similar phenomenon especially allergic phenomenon, is of the greatest importance. The discoveries of Hoffman have opened new routes to medical progress." (H.A. Abramson, 1965)

5-HT is one of the main ingredients in the toxins of scorpion, bee, and wasp. The allergic phenomenon caused by insect stings is thought to be due to the overactivation of 5-HT and histamine pathways. Several experiments in the 1950s suggested that LSD could be of use when catecholamine pathways become abnormally activated, because it blocks the effects of 5-HT. For example, in 1955, it was shown that LSD administration prevented death by prophylactic shock by 5-HT. LSD given 15-60 minutes before inhalation of an aerosol spray of 5-HT prevented respiratory failure in guinea pigs, by preventing the 5-HT-induced contraction of bronchial muscles and shortness of breath (H. Herxheimer, 1955). In 1958, Cerletti and colleagues showed that LSD blocks 5-HT-contraction of smooth muscle preparations (A. Cerletti, 1958), and that LSD has the ability to prevent 5-HT-swelling in rat paw (W. Doepfner, 1959). Abramson may have been familiar with work by Cerletti and Herxheimer, and as a clinician he was interested in the possibility of using LSD and methysergide to antagonize 5-HT, which has been implicated in the vascular pressure and etiology of migraines. Abramson wrote,

“UML-491 is the best drug known for the prevention of certain headaches, many of which may be of allergic origin. The antiserotonin activity of UML is among the highest of certain LSD congeners and derivatives of LSD… the relationship of these drugs to their anti-serotonin activity is of particular interest to the allergist because of the way in which the congeners and derivatives of LSD block the action of serotonin on smooth muscle.” (H.A. Abramson, 1979)

Abramson cited the huge disservice done to the medical community by associating LSD with brain damage, when successful uses of LSD to treat migraine and alcoholism had been identified.

“It seems important to stress at this time that many derivatives of LSD play a most important role in medical treatment. To label any one of these derivatives as the cause of “chronic brain damage” without direct evidence, validated statistically, constitutes a disservice to science and to the practice of medicine… Let us hope that the anxieties of a small group will be replaced by a more hardy spirit of inquiry and scientific investigation.” (H.A. Abramson, 1964)

Towards the end of his research career, Abramson began to have some interesting ideas about the relation between electronic desaturation of certain molecules and drug psychosis-producing ability. In certain hypnotic drugs, he pointed out that if a double bond is present in an unsaturated hydrocarbon, the unsaturated compound is more active than the saturated analog.

"The study of derivatives of arachidonic acid might be another part of the still undisclosed chemical mechanisms which produce mental illness in man.” (H.A. Abramson, 1979)

Reference

HERXHEIMER H. (1955). The 5-hydroxytryptamine shock in the guinea-pig. The Journal of physiology, 128, 435-445.

CERLETTI A. and W. DOEPFNER (1958). Comparative study on the serotonin antagonism of amide derivatives of lysergic acid and of ergot alkaloids. The Journal of pharmacology and experimental therapeutics, 122, 124-136.

Abramson H. A. The use of LSD in psychotherapy. Transactions of a conference on d-lysergic acid diethylamide (LSD-25). Madison Printing Company: Madison, New Jersey, 1959.

ABRAMSON H. A. (1964). Antiserotonin Action of Lsd-25 and Other Lysergic Acid Derivatives: Fact and Fiction. The Journal of asthma research, 15, 207-211.

Abramson H. A. and A. Rolo (1965). Lysergic acid diethylamide (LSD-25). 38. Comparison with action of methysergide and psilocybin on test subjects. The Journal of asthma research, 3, 81-96.

Abramson H. A., H. H. Gettner, P. A. Carone, A. Rolo and L. Krinsky (1979). The intracranial injection of drug in goldfish. I: Hallucinogens and their antagonism to smooth muscle activity. The Journal of asthma research, 16, 55-61.

Abramson, H. A. and H. H. Gettner (1979). Double bonds, aliphatic chains, and hallucinogens, updated. The Journal of asthma research, 16, 120.

What are hallucinations?

Nothing that can be imagined is unreal.

Everything that is imaginable exists,

and is an object or thing or texture somewhere.

Dreams or hallucinations may be significant to "reality" for transcendental idealists and others who believe that what you perceive is the product of an intrinsic process and not a part of the external physical reality.

Delysid

A note on the LSD product.

"Small ampules of LSD 25 (Delysid) were used, each containing 100 ug, a new ampule being opened for each experiment." (H. Ursin, 1962)

There was a stretch of time when Sandoz was the only company that manufactured LSD. They called it "Delysid". Nearly all the scientific researchers of that time sourced their LSD from Sandoz. Though chemicals are supposed to be chemicals whether ordered from Pfizer or Merck, the singular source of Delysid, described here and elsewhere as small glass ampules containing 100 ug, cannot be overlooked. It serves as an important control for the research conducted during that time period, and greatly facilitates comparison between studies. There is little concern that drug purity would be a factor to account for different results between studies.

Reference
URSIN H. 1962. The lack of effect of LSD 25 on amygdaloid and cortical attention responses Psychopharmacologia, 3, 317-330.

Gap junction coupling in the development of the nervous system

Gap junctions have long been recognized as prevalent and important in embryological brain development, but gradually diminish in number, and presumably importance, as the brain matures.

Gap junction coupling between cells probably serves an organizational role for the beginning stages of development. In the developing cortex, before the formation of large numbers of chemical synapses, the coordination of groups of cells is mostly achieved by the conduction of inositol triphosphate IP3/Ca2+ waves (a biochemical action potential) through gap junctions, rather than by transmission of Na+-based action potentials. Many studies in rats have shown that gap junction coupling abruptly diminishes by postnatal week 2-3. As shown in the figure below, there is a significant amount of gap junction coupling in the rat neocortex at P5 (A) and P7 (B), as compared to just 8 days later, at P15 (C). Then there is a precipitous decline in gap junction coupling to practically nil. No strong gap junction coupling is detectable after P16 in rat, which corresponds with the end of the second postnatal week (A. Peinado, 1993).

From Gap junction

There are definitely more gap junctions open during the early stages of development for example, it is easy to detect dye-coupling in embryonic and young animals as compared to adults. The figure below shows a decrease of dye-coupling by two weeks postnatal in rat, when no dye-coupling was observed between deep layer pyramidal cells.

From Gap junction

The switch from gap junction to synaptic activity
 

Gap junction coupling and synaptic transmission co-exist in the rat neocortex for the first week postnatal, but by the second week, much less gap junction coupling can be detected. There is an abrupt switch from gap junction coupling to primarily synaptic coupling, as shown in the figure below. 

From Gap junction

In developing ferret visual cortex, there is an inverse relationship between dye coupling and synaptic activity, and the loss of gap junction coupling establishes the time for the onset of synaptic activity. Uncoupling of gap junctions might be a prerequisite for the establishment of synaptic connections, because when the percentage of coupled cells drops, the spontaneous synaptic activity increases threefold (K. Kandler 1998). An increase in spontaneous firing is reflected in a change in the pattern of EEG components. Slower components (2-4 Hz) began to increase near the end of the second postnatal week. Fast components emerge at the end of the third postnatal week, and the EEG mostly resembles the adult rat by the third week.

Gap junction coupling is significant because every vertebrate goes through a period of intense coupling (gap junctions between two cells open) during embryonic development, and coupling is thought to involve, to a certain extent, every cell in the network. Since gap junction coupling is more frequent in the womb and in younger animals, it has been postulated that the function of coupling is to improve coherence between desynchronized cells. Gap junction coupling is expected to be small when the voltage difference between cells is small (when cells almost synchronized), and large when cells are not synchronized.

There is a considerable amount of cellular membrane in the dendritic arbors of just 1 neuron. It could be imagined that gap junctions allow for these swaths of cellular membrane to connect to each other and grow ever larger. Very extensive electrotonic coupling decreases neuronal input resistance and counteracts the ability of individual cells to generate large potential changes, thus keeping all the cells in the network on the same page. This shunting effect might be the reason for the virtual absence of evoked epileptiform discharges observed in slice preparations made from rat neocortex during the first week of postnatal development.

Gap junction coupling may reach a critical mass when too many cells become coupled, and suddenly by the end of postnatal week 2-3, many neurons in the rat become uncoupled. A mechanism is needed to reduce gap junction coupling in the network at this critical time. One explanation is that, at the end of postnatal week 2, there is a sudden innervation of the cortex by 5-HT fibers from the dorsal raphe nucleus in the brainstem. The neurotransmitter 5-HT has been shown to promote gap junction decoupling between developing somatosensory cells in pyramidal neurons, reducing the number of electrical synapses between cells, and it has been shown that 5-HT promotes gap junction decoupling via the 5-HT2A receptor (B. Rorig 1996).

However, 5-HT is by no means the only molecule that is capable of uncoupling gap junctions. Many different signaling molecules, with widely varying chemical structures, lead to uncoupling of gap junctions.

Reference

Peinado A., R. Yuste and L. C. Katz 1993. Extensive dye coupling between rat neocortical neurons during the period of circuit formation. Neuron, 10, 103-114.

Rorig B. and B. Sutor 1996. Serotonin regulates gap junction coupling in the developing rat somatosensory cortex. The European journal of neuroscience, 8, 1685-1695.

Kandler K. and L. C. Katz 1998. Relationship between dye coupling and spontaneous activity in developing ferret visual cortex. Developmental neuroscience, 20, 59-64.

Bipolar neurons of the thalamic reticular nucleus (TRN)

The reticular nucleus of the thalamus (TRN) is a large and thick layer of grey matter which surrounds the thalamus, separating it from the striatum and the corona radiata. It is well known that the TRN plays a key role in the control of rhythmic EEG activity in the mammalian brain, particularly during sleep.

What does a TRN cell look like?

Lucifer yellow-filled TRN neurons with fusiform and bipolar shape are shown below.

From TRN, thalamic reticular nucleus

TRN neurons have thick dendrites extending from the soma. These dendrites measure 2-5 um in diameter, and are 200-500 um in length. TRN cells have a high input resistance, from 70 to 500 Mohms.

An electron micrograph of a TRN neuron shows its cell body adjacent to a blood vessel (star), suggesting a neuron-vasal relationship.

From TRN, thalamic reticular nucleus

This is significant because TRN neurons might belong to a class of neurons referred to as primary sensory neurons, which typically exhibit dendrite-vasal relationships. In context of their putative membership in this special class of neurons, TRN neurons may be capable of sensing and responding to changes in blood conditions (e.g. oxygen, pressure) nearby to the important thalamic brain structures.

Like other primary sensory neurons, the dendrites of TRN neurons form dendrite bundles.

From TRN, thalamic reticular nucleus

References

Baars B. J., W. P. Banks and J. B. Newman. Essential sources in the scientific study of consciousness. MIT Press: Cambridge, 2003.

Pinault D. (2004). The thalamic reticular nucleus: structure, function and concept. Brain Res. Brain Res. Rev. 46, 1-31.

History of chlorpromazine

Chlorpromazine is dimethylaminopropyl-chloro-phenothiazine.

From molecules

Forerunners of chlorpromazine were promazine and diethazine. (A.E. Caldwell, 1970)

From molecules

Chlorpromazine was first synthesized in 1950. Though many drugs like LSD and aspartame are chance discoveries, chlorpromazine may be regarded as an example of drug engineering.

In its initial uses, chlorpromazine was given for postoperative shock or severe traumatic shock. In combination with small amounts of weak general anesthetics, chlorpromazine allowed surgeons to perform major operations, that were not possible with the use of general anesthetics alone. In order to prevent surgical shock, the entire autonomic nervous system must be inhibited. Chlorpromazine is an autonomic stabilizer, an adrenolytic, parasympatholytic and nearly non-antihistaminic phenothiazine that has great central activity with relatively low toxicity.

Subsequently chlorpromazine gained a reputation as an antipsychotic drug. The clinical reports agree in large measure that chlorpromazine appears to be useful in the management of agitation and manic states in psychoneurotic patients. Clinical reports from 1955 reveal the novelty and effectiveness of chlorpromazine at that time. Bleuler and Stoll wrote,

"... reserpine and chlorpromazine soothe and relax patients to an extent formerly unknown to the doctors writing this report ... after 2-3 days of excessive sleeping, from which the patient can be awakened, the patient's mood is more indifferent, less impulsive, quieter, and more relaxed." (M. Bleuler, 1955)

Chlorpromazine has been beneficial in a variety of conditions presenting a picture of psychomotor excitement. It is considered to be an advance over sedating drugs or physical restraints, but has been largely replaced by the newer drugs haloperidol and risperidone.

The physician will probably say that the sedative effect of chlorpromazine is not associated with clouding of consciousness, impairment of judgment or disinhibition of affect; that chlorpromazine can reduce severe anxiety, diminish phobias and obsessions, reverse or modify a paranoid psychosis, quiet manic or extremely agitated patients, and change the hostile, agitated, demented patient into a quiet, easily managed patient. After chlorpromazine treatment, psychotic patients tend to lose interest in their preoccupations, delusions, and hallucinations, and for lack of interest in those, they may eventually subside.

Less is known about the subjective effects of chlorpromazine. It cannot be labeled as an addictive drug by any means, because oftentimes patients do not comply with taking it. Chlorpromazine is not considered to be a drug of abuse. It is not reported to cause euphoria.

According to Caldwell, chlorpromazine is one of the most important drugs in the treatment of wild animals and in their relocation to preserve wildlife.

In 1954, it was thought that chlorpromazine might block the effects of LSD or mescaline. However, some humans have reported an unpleasant intensification of LSD effects when combined with chlorpromazine or reserpine. Ketanserin appears to be a much more specific and effective drug for antagonizing LSD and mescaline intoxication than chlorpromazine.

The average daily dose of chlorpromazine is 300-500 mg by mouth, which is equivalent to a dose of 75-150 mg intramuscular. If chlorpromazine is given intravenously it must be diluted with glucose to avoid irritation with the venous walls.


Reference

Caldwell A. E. Origins of psychopharmacology, from chlorpromazine to LSD. Charles C. Thomas: Springfield, 1970.

Dendrite-vasal relationships

Golgi had observed that dendrites often terminate close to blood vessels, and he suggested that dendrites might be involved in nutritive functions, as an extension of his theory that dendrites form a continuous reticulum in the brain. The reticulum theory was rejected in favor of the neuron doctrine, relegating the dendrites to receiving centers for information coming from the axon, yet the importance of dendrites in microcirculation and gap junction communication between neurons has received new attention by Sotnikov and others. Figure 8 below illustrates the relationship between blood microvessels and dendrites of Sotnikov's primary sensory neurons, which are a class of neurons with dendrites that respond to photic or mechanical stimuli. Cortical interneurons (IN) are pictured on the left, with dendrites branching on capillaries (C). Its axon synapses on a pyramidal neuron (PN). A Lugaro cell is shown on the right, with dendrites that branch near microvessels (V) and Purkinje cell bodies (PC). According to Sotnikov, the dendrite-vasal situation was noted in the cerebellar cortex in cells first described by Lugaro in 1894.

From 06Sotnikov

Another group of neurons whose dendrites have a close relationship to blood vessels are found in the raphe nuclei. In Figure 5 below, a raphe neuron with bipolar shape and thick dendrites branches onto a capillary.

From Dendrites

Raphe neurons form dendrite bundles near the basilar arteries, as depicted in Figure 3 (below). A vertical arrow marks the midline. Two large basilar arteries carry fresh oxygenated blood to the brain, so the amine-laden dendrites are positioned to release 5-HT into the bloodstream to the brain in order to regulate blood partial pressure O2 (pO2) levels. It has been established that raphe dendrites respond to changes in pO2 levels, and 5-HT has famous vasoconstrictor actions, representing a reflex arc.

From Dendrites

In the figure below, the dendrites and soma of raphe neurons appear to contact the basilar artery on each side of the midline. Individual dendrites were observed contacting one or more underlying blood vessels. Electron microscopy techniques were used to show the close apposition of blood vessels with neuronal perikarya and dendrites of medullary raphe neurons, and no intervening glia were reported.

From Dendrites

Raphe dendrites could be stretched as the blood vessels constrict and dilate. Electrophysiologists who have inserted glass pipettes into the raphe neurons have noted that the raphe nuclei can be verified by the presence of characteristic blood pressure responses upon stimulation.
Dendrite-vasal relationships occur in various regions of the brain. Blood vessels adjacent to dendrites have been described in cortex, locus coruleus, substantia nigra, reticular thalamic nucleus, and hypothalamus. The dendrites adjacent to blood vessels often store amine-rich vesicles and are very active in protein synthesis. Hypothalamic magnocellular neurons have dendrites that secrete vasopressin and oxytocin into the blood stream, which are chemicals that are known to affect water balance and mood, thus many important functions are under control of the secretion products of dendrites.
Dendrite-vasal relationships in substantia nigra are notably absent from Parkinson's patients. Overall length and thickness of dendrites of cortical pyramidal neurons are reduced in older animals, when cognitive decline sets in, highlighting the possible importance of dendrite connectivity (thickness and length) in consciousness.

"The melanin-containing neurons of pars compacta in normal substantia nigra have a close spatial relationship with the intrinsic blood vessels. The walls of the substantia nigra capillaries fused to the plasmalemma of the nigral perikarya and dendrites. However, this neuronal-vascular relationship was not present in the brain stem of patients with Parkinson's disease." (J.P. Cummings, 1979)

Reference

Scheibel M. E., U. Tomiyasu and A. B. Scheibel. (1975). Do raphe nuclei of the reticular formation have a neurosecretory or vascular sensor function? Experimental Neurology, 47, 316-329. 10.1016/0014-4886(75)90260-5

Cummings J. P. and D. L. Felten. (1979). A raphe dendrite bundle in the rabbit medulla. Journal of Comparative Neurology, 183, 1-23. 10.1002/cne.901830102

Brain lesion

About brain lesions in general.

"One of the oldest and still most important techniques for studying neurons in aggregate is to destroy all of the cells in one small region of the brain and then to observe how brain operation is altered as a result of the lesion. Lesion is used as a noun to indicate the area of destroyed cells and also as a verb to denote the act of destroying cells; From the nature of the change in brain function, together with other types of evidence, it is often possible to assign a role in nervous system operation to neurons in the area destroyed. Quite frequently, some function of the brain will be lost completely: for example the animal may be blind, or deaf, or unable to move a limb after the brain area has been destroyed. In such cases of a deficit following the loss of cells in a specific area, it is usually inferred that those cells were intimately involved in performing the lost function. Some lesions do not cause deficits, but rather result in exaggerated performance of some operation. For example, destruction of cells in a particular area of the hypothalamus leads to almost continuous eating and to enormous increases in body weight. Such an increase in a type of behavior is known as a release phenomenon, and is taken to indicate that the cells which were destroyed normally serve to inhibit other neurons responsible for the behavior which has become exaggerated. " (C.F. Stevens, 1966)

Reference

Stevens, C. F. 1966. Neurophysiology: a primer. John Wiley and Sons, New York.

you or your memory

YOU OR YOUR MEMORY

Putting aside for a moment the short-comings of Aristotelian two-value logic, "A thing is either A or not-A", we can think of the brain as sustaining the activity of cells whose firing represents information derived from 1) readout from long-term memory or 2) brief sensory input.

Our perceptions of reality are limited by what we can perceive with the brain. We can think of reality as a blend of:
1) MEMORY: readout from long-term memory
2) INPUT: brief sensory input

MEMORY
"Memory” is the brain program that is capable of responding to specific, predictable stimulus inputs, and has sometimes been referred to as being unconscious. The example of driving along a familiar route has been used by many authors to describe this type of memory.

"Whilst driving home from work our conscious minds may be busy reviewing the events of the day whilst at the same time, we are watching traffic, changing gear, following the road but are unaware of any of these operations. Yet if we encounter a hazardous situation - such as a child in the road - we instantly become aware of the child, the road, the motor operations of driving, and thereafter slow down to drive more carefully under conscious control. Our conscious mind seems to take over the control of our body in these situations." (J. McFadden, 2002)

In other words, there may be some unexpected events that happen on the way to work, but things generally proceed as expected, based on what the memory program computes to be most probably out there.

The information in the adult brain largely depends on this dense and unconscious memory. Timothy Leary said that the individual world each person occupies is his reality tunnel. In the reality tunnel mode of operation, the adult brain can screen out unfavorable stimuli which are present in the environment. For example, the memory of a crack addict may construct a reality in which a crack pipe is more significant than the baby in the same room. In this reality tunnel mode of thinking, it is possible to confuse our expectations with reality.

However, activation of "memory" programs during sustained wakefulness never achieves total autonomy from the stimulus environment, because we always encounter children in the middle of the road, unforeseen traffic delays, and accidents.


BRIEF SENSORY INPUT
"Input" is the brain program that is activated by the arrival of certain unpredictable stimuli. Activation of the "input" program during wakefulness never achieves total autonomy from "memory".

-->

There is far more information out there than the mind can behold. The brain only samples a fraction of the information out there and then it fills in the rest. The sampling of information "out there" is accomplished by the input program, while its left up to memory to fill in the rest. To the extent that memory is successful, brief sensory input will be put on hold.

During adulthood in mid-life, when we have a strong sense of memory, we are merely the brain that looks at the universe. The beauty is there, but it is the expected kind. When we forego as many expectations as possible at the beginning and end of life, we are more likely to turn on to the input, and the weirdness of the big existence. . . . Terrence McKenna referred to the Input program as an alien intelligence, "Whatever you think it is, its not what you think it is."

A hypothesis about LSD and the 2 modes: memory and brief sensory input

It seem likely that LSD has a powerful dismantling effect on memory, defined above as the reality tunnel existence in which most adult human beings operate. Anyone who has taken LSD may have experienced firsthand the uncomfortable feeling of abulia in place of a normal sense of confidence of "who I am".

LSD may cause a failure of the cortex to predict what is out there, when you begin to see things of undescribable beauty which you have never possibly seen before in your entire life. So, without prediction to guide us, nearly all experience becomes reactive and primitive. It could be hypothesized that LSD turns on the "input" brain program, or else that it turns off the "memory" brain program. Either way it leaves the impression of an influx of sensory information, followed by a reorganization of the "reality tunnel" brain program. Studies in pigeon and rabbit have shown that low doses of LSD facilitate certain types of sensory awareness that get translated into new memory. Memory of the LSD experience does not differ much from memory of any memorable event. Afterall what is an LSD flash-back besides a powerful memory recollection?

Primitive learning may happen so effectively under LSD that we caution people about making good choices about the "set" and "setting", the people and stimuli who are present when tripping.

LSD and other hallucinogens seem to be able to enhance certain types of learning without necessarily promoting the intent to learn (over achievers take note). Loss of ego functioning does not necessarily prevent memory formation, because much learning takes place without being conscious of the details (e.g. language acquisition in children).

The facilitation of a new learning experience can help people to break out of addiction, or other memory programs that have become toxic.

"[Under the influence of LSD] other types of learning may be unimpaired and may be much improved. If this were not so, the psychedelic experience would help no one. A large number of alcoholic subjects learn concepts and ideas in a few moments that they had not grasped for years. These are termed flashes of Inspiration or Insight but they seem to me to be the acquisition of new concepts. One subject, a brilliant physician alcoholic, prided himself on the fact he took no drugs. Under LSD he vividly learned alcohol Is a chemical and, by his old definition, a drug. Other subjects learned understanding, tolerance, compassion, the meaning of psychotic fear, etc." (A. Hoffer, 1956)

Summary

For convenience I have described reality as a blend of memory and brief sensory input, but Phillip K. Dick reminds us that Aristotelian two-value logic is fucked. Afterall, how would a physical reality that is separate from the mind exist when the brain emerged from this order? To quote Sherrington's pupil,

"It is not the code or the message coming from the outside world that is being transmitted, but rather it is the neuronal element that responds to the message from the outside that is itself the message! " (R. Llinas, 2001)

This complicates the definition of the "input" program as having sampled something from the "outside", and is the point in the conversation when people like to mention "intrinsic properties" related to certain Ca2+ conductances.

At one extreme, the brain is capable of emulating reality in the absence of input from such reality, and at the other extreme, sensory contents gain internal context. Like the immune system, the brain may keep a border between the self and the environment, the function of which enables sensitization to the environment with time.