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Sunday, September 12, 2010
Free radicals, relation to the EEG
The electric currents of the brain are subject to change. Free radicals, which by definition have an unpaired electron, have a direct effect on EEG rhythms. This was studied in 1969, when Polis showed that intravenous administration of free radical proteins in rabbits implanted with chronic EEG electrodes and sedated with pentobarbital led to sudden EEG arousal indicative of brain excitation. (B.D. Polis, 1969). These findings suggest the involvement of free radical structures in energy transfer in nervous tissue.

Wait a minute, you mentioned free radical proteins. Tell me again, what is the difference between a normal protein and a free radical protein?

Ok, I shall give you the answer by explaining more about the experiment done by Polis and colleagues. Nitrosyl disulfonate, NDS, is a very good oxidizing agent that was used to convert certain amino acids to stable free-radical form. Potassium NDS is a bright orange diamagnetic salt which dissolves in water to form a blue-violet paramagnetic ion; NDS oxidizes albumin to radical albumin, two species with different UV and ESR spectra. Radical albumin is characterized by the appearance of an absorption band with a broad shoulder at 490 mu, and a shift of the 278 protein band, as shown in Figure 1.

From 69Polis



As shown in Figure 2 below, free radical albumin has a higher ESR signal than normal albumin, indicating that there is a higher concentration of unpaired electrons associated with radical albumin protein.

From 69Polis


Polis found that the free radical albumin with its higher concentration of unpaired electrons had more excitatory EEG effects than regular albumin protein. The 2 figures above represent the spectra of albumin and free radical albumin, however the most pronounced EEG changes were observed with NDS-treated bovine growth hormone protein and NDS-treated 5-hydroxytryptophan. NDS treatment of proteins was essential for producing the "alert EEG" effect; in control experiments with normal rabbit serum albumin or 5-hydroxytryptophan, the researchers observed periods of increased sedation to the point of favoring sleep in the rabbits.

The demonstration that electron-excited molecules (free radicals) can induce brain excitatory effects, or alert rabbit EEG, was compared to the LSD-induced alert EEG in rabbits. Polis wrote,

“...this situation resembled the effects in rabbits following administration of LSD. However, in contrast to the prolonged and sustained hyperstimulation induced by the hallucinogens, the periods of extreme stimulation with free-radical compounds were of relatively short duration and lasted in the order of 1-5 minutes at most.” (B.D. Polis, 1969)

A prolonged time course of action was a common feature of LSD-induced "alert EEG" and free radical protein "alert EEG". The free radical in vivo effects required a period of latency which lasted from 4-15 minutes before arousal took place. LSD exhibits a similar effect on the brain, where the strongest effects are delayed by as long as 60 minutes.

Another method for converting normal proteins to free radical form is to expose the protein to light. Free-radical derivative of crystalline rabbit serum albumin which has been illuminated by light has a larger ESR signal, and the increase in free-radical concentration observed by ESR measurements was associated with increased brain arousal properties.

From 69Polis


Have there been other experiments which showed a similar result as Polis?

Yes. In research published in the same year, 1969, Gooley and colleagues showed that the pharmacological effects of chlorpromazine depend on the free radical form, in white mice. Chlorpromazine complexed with SO2 had a hypothermic effect of approximately double the dose of pure chlorpromazine, while the period of sedation was extended by about 50 per cent. Likewise, ultraviolet-irradiated chlorpromazine caused a larger temperature drop in mice than pure chlorpromazine.

“Chlorpromazine hydrochloride radicals were produced by ultraviolet irradiation of aqueous solutions and also chemically by formation of an electron charge transfer complex with sulphur dioxide (SO2), a good electron acceptor. The stoichiometry of the complex is 1:1” (C.M. Gooley, 1969)



References

Polis B. D., J. Wyeth, L. Goldstein and J. Graedon. (1969). Stable free-radical forms of plasma proteins or simpler related structures which induce brain excitatory effects. Proc.Natl.Acad.Sci.U.S.A. 64, 755-762.

Gooley, C. M., H. Keyzer and F. Setchell 1969. Free radical drug enhancement. Nature. 223, 80-81.
Posted by LSD Research at 8:57 AM 0 comments
Saturday, June 12, 2010
Abramson's "Cold Spring Harbor Questionnaire" for human LSD research

“One of the serious objections to questionnaires is that the validity of individual items is doubtful. Nevertheless, there are many items whose validity cannot be pushed further than a subjective response. Unfortunately, the only way to tell whether a person has hallucinations, or a headache, for that matter, is to ask him. As our science progresses, more objective tests for these phenomena may be evolved. In the meantime, it would seem that the proper course for the scientific psychologist to follow lies somewhere between complete dependence upon verbal reports of individuals and complete rejection of such material." (M.E. Jarvik, 1955)


Many of the workers who have studied mescaline or LSD intoxication have been puzzled at the subjects. Their attitude seems to be one of an interested spectator whose planned action is waived for the duration of the show. Efforts of the investigator to involve the subject in organized activities, such as answering questions, may be answered with reluctance or frank refusal whereas a verbal account of the experiences may be given more freely.

Even though the questionnaire technique is not always reliable, it has been valuable in connection with psychoactive drug research to assess the relative potency of LSD and LSD congeners in humans. The most common questionnaire used is the Cold Spring Harbor Questionnaire, shown below.

From lsd dose


The 59-item questionnaire has short questions like, "Do you feel unsteady?" and "Are you anxious?". In 1955, Jarvik and Abramson found that LSD led to a large number of positive responses on the Cold Spring Harbor Questionnaire, and far more positive responses than the drugs LAE-32, BOL-148, ergonovine, scopolamine, alcohol, methamphetamine (methedrine), and two placebos. The subjects were 5 nonpsychotic volunteers, who received all drugs on different occasions. Questionnaires and physiological tests were given during the drug effects. As shown in the results below, LSD produced the most positive responses on the questionnaire of all the drugs tested, thus validating the usefulness of the Cold Spring Harbor questionnaire for LSD research.


From lsd dose


Not only did LSD produce the most positive responses on the questionnaire, it was the study drug with the smallest dose by weight. The concentration of alcohol was about a million times as great, expressed in terms of weight, as the concentration of LSD, as shown in the figure below.


From lsd dose


“In comparing the effects of seven different chemical and two tap water placebos upon the responses to a questionnaire, it is apparent that the chemical structure of the compound ingested is of paramount importance in determining responses to these questionnaires.” (M.E. Jarvik, 1955)


An abbreviated version of the questionnaire with 47 items was used with much of Abramson's human LSD research. The Table below gives the questions and responses by 26 volunteers, at 0.5 h, 1.5 h, 2.5 h, and 3.5 h after LSD ingestion. The questions that frequently gave a "yes" answer were, "Is salivation increased?", "Do you have a funny taste in your mouth?", "Is it a bitter taste?", "Does your head ache?", "Do your hands and feet feel peculiar?", "Is there pressure in your ears?", "Is your hearing abnormal?", "Do you tremble inside?", and "Are you anxious?"

From lsd dose


The test situation asking a subject to respond to these questions has turned out to be relevant to certain basic questions.



References

JARVIK M. E., H. A. ABRAMSON and M. W. HIRSCH. (1955). Comparative subjective effects of seven drugs including lysergic acid diethylamide (LSD-25). J.Abnorm.Psychol. 51, 657-662. 10.1037/h0041073

Abramson, H. A., M.E. Jarvik, M.R. Kaufman, C. Kornetsky, A. Levine and M. Wagner 1955. Lysergic acid diethylamide (LSD-25): I. physiological and perceptual responses. J Psychol. 39, 3-60.
Posted by LSD Research at 11:51 PM 0 comments
Sunday, March 07, 2010
Habituation

In a paper to the Psychological Bulletin, J. Donald Harris used the word "habituation" to refer to behaviors of accommodation, inhibition, extinction, stimulatory inactivation, acclimatization, negative adaptation, etc. He called habituation a "law of forgetting," a respite from sensory stimulation.

From Protista to man,

"Perhaps the most ubiquitous phenomenon in animal behavior is that of response decrement as the result of repeated stimulation." (J.D. Harris, 1943)

A great number of stimuli will cause Ameba (Rhizopoda) to cease protoplasmic streaming, and if the stimulus is continuous and not too intense, the streaming will shortly begin anew.

"Ameba react negatively to tap water or to water from any foreign culture, but after transference to such water they behave normally."

Paramaceium soon becomes acclimatized to an energy pattern which ceases to change, whether it be chemical, thermal, photic, or electrical. However, habituation occurs when stimuli are weak, but not if the stimuli is too intense. Habituation does not occur under the condition where the environmental change is becoming lethal. Thus, Paramecia dropped into an injurious chemical solution will dash about till necrosed.

Certain Hydra are much more active than others in habituating, although somewhat similar results are obtained from all species. Hydrozoa spread their highly-colored discs near the surface of the water. A drop a water falling from a height of 30 cm causes the animal to react, but rarely to the second and third drop and infrequently the fourth drop.

Mosquita larvae come to the surface of water in sunlight, and if a shadow passes over they swim towards the bottom. Yet after a number of shadows, few larvae are seen to dive.

A case report of habituation in a spider,

"Not until she had fallen out of the web 22 times, at the approach of the [tuning] fork, could she restrain the impulse to drop. It was apparent, however, after the seventh or eight time, that she was less startled by the sound than at first, since the distance that she fell and the period of time that elapsed before she returned to the web grew shorter and shorter in the later experiment. At first she fell 15 or 18 inches, and remained at the end of her line for several minutes, while toward the last she fell only an inch or two, and immediately ran back to her web. After the twenty-second trial she only held up her legs as the fork approached. Finally, completely worn out and disgusted, she retreated to a neighboring branch, drew in her legs, and remained sullenly unresponsive to all further attempts."

Harris's accounts of response decrement in these organisms cannot be explained by a decrement in reflexes containing intermediary neurons. Explanations given in terms of homeostasis are unsatisfactory, wrote Harris, and,

"Habituation due to changes in the strength of synapses cannot apply in Protozoa. Current theories of long-term potentiation at a synapse do nothing more than roughly to suggest the locus of the phenomenon."

Sixty-five years after Harris, enormous effort has been spent trying to understand how, when, why, and by what mechanisms chemical synapses can be modified, yet a complete explanation of memory in terms of dendritic spine stability and changes in synaptic transmission is still forthcoming. Rodolfo Llinas spent more than the past 40 years studying synaptic transmission of the giant squid synapse, and he wrote,

"There are many elements of nature, completely lacking a brain in a traditional sense, which still have a peculiar amount of intelligence." (R. Llinas, 2002)



References

Harris, J. D. 1943. Habituatory response decrement in the intact organism. Psychol Bull. 40, 385-422.

Llinás, R. R. 2002. I of the vortex. MIT Press, Cambridge.

Posted by LSD Research at 4:50 PM 1 comments
Labels: habituation
Thursday, February 18, 2010
The Wada test

"A perfectly bilateral machine or organism could not perform left-right discriminations, which much include scanning in a preferred (e.g. left-to-right) direction and distinguishing between such letters as d and b, p and q and such words as saw and was, such organisms could only make mirror-image responses to mirror-image stimuli..." (J.L. Bradshaw, 1983)


The right hemisphere is biased toward global processing and the left for local processing. Robert Sperry listed the following specializations for the right hemisphere: rhythm, spatial awareness, Gestalt (the whole picture), imagination, daydreaming, color, dimension. This supposedly describes the creative right brain of many left-handed artists. The left hemisphere, which controls the right hand - typically the dominant hand for writing the name - and which has a higher ratio of grey to white matter than the right hemisphere, specializes in verbal-linguistic and analytic functions.

Many techniques have been developed in the field of left-right brain research, but the Wada test must be one of the most dramatic and conclusive experiments. During a surgical procedure where the large arteries leading to the brain are exposed, injection of drugs into the bloodstream will selectively anesthetize one hemisphere. The Wada test is not performed very often, but it might be used before major brain surgery to determine which hemisphere is dominant for language.

From Human cerebral asymmetry, J.L. Bradshaw writes,


"Wada (1949) first developed the procedure known as the Wada test: an injection of the barbiturate sodium amytal (amobarbital) into one (left or right) of the common carotid arteries that supplies its ipsilateral hemisphere. A temporary loss of function is produced on the affected side of the brain: a flattening of the EEG, along with hemiparesis, hemianesthesia, and hemianopsia. It is in effect a reversible hemispherectomy, permitting tests of higher mental functions in the other hemisphere. If the drug is injected into the dominant hemisphere, there is usually total and abrupt cessation of speech. In view of the slight but definite risk accompanying the insertion of the needle or catheter into the carotid artery, the Wada test is employed only when absolutely necessary, and consequently such patients usually have more or less severe existing abnormalities of cerebral function. Moreover, since the unilateral suppression lasts only five to ten minutes and the experience itself is probably disturbing to the patient, usually all that can be determined is which hemisphere is specialized for speech production. Typically, the upraised contralateral arm and leg fall to the bed with a flaccid paralysis a few seconds after the injection. If the injected hemisphere is nondominant for speech, there is an abrupt and more or less total cessation of speech shortly after the injection; it lasts until recovery from the hemiparesis is well advanced. The patient makes characteristic dysphasic responses (perseveration, misnaming, mixing up the sequence of numbers and of days of the week, etc.) for several minutes before speech returns to normal. The Wada test has shown that dextrals have clear left hemisphere language dominance in over 90 percent of the cases, and sinistrals in 70 percent of cases. The effects of unilateral ECT are similar to those of unilaterally injected sodium amytal." (J.L. Bradshaw, 1983)


Depression of the left hemisphere with the Wada technique is associated with a depressive catastrophic reaction and for most people the traumatic loss of speech. Depression of the right hemisphere with sodium amytal leads to a euphoric or manic response.


Reference

Bradshaw, J. L. and N. C. Nettleton (1983). Human cerebral asymmetry. Prentice-Hall, New Jersey.

Posted by LSD Research at 9:42 AM 0 comments
Monday, February 01, 2010
BOL-148

BOL-148 is the 2-brom derivative of LSD. There is a bromine in place of hydrogen at position 2.


From molecules


In spite of its close structural relationship to LSD, BOL-148 has no psychedelic effects. In 15 healthy males, doses of 75-110 ug/kg BOL-148, which 100X exceed an effective dose of LSD, caused no change in pupillary dilation, patellar reflex, or blood pressure (H. Isbell, 1959). BOL-148 did not alter the behavior of 6 individuals with schizophrenia, when given at 10X the dosage of active LSD, although for BOL-148 these doses may have been too low to observe any effect. One mg BOL-148 twice a day for 2 weeks, or 5 mg for 3 days had no evident effect on their psychoses (W.J. Turner, 1958).

With newly developed drugs and low doses of known drugs, there is frequently a problem in deciding whether the drug has an effect on the EEG. LSD is one of the most potent drugs known to affect the electrical potentials of the brain, while doses of 100+ ug/kg BOL-148 are reported to be without effect on the EEG. There was no sign of the fast electrical activity or alerting behaviour seen with injections of LSD in cats, even when doses of up to 100 ug/kg of BOL-148 were used intraventricular (P.B. Bradley, 1956). BOL-148 produced no EEG changes in Macaca mulatta, in high dose ranges 110-175 ug/kg (R.R. Monroe, 1961). Saline gave the same response as 1000 ug/kg BOL-148 in cats with permanently implanted EEG electrodes (E. Eidelberg, 1965). In rabbits, 500 ug/kg BOL-148 failed to produce EEG alerting for longer than 15 minutes (A.K. Schweigerdt, 1966).

BOL-148 has a very slight change in molecular structure compared to LSD, but it has none of the behavioral effects of LSD. When LSD or BOL-148 were administered intraventricularly to cats, LSD caused behavioral arousal whereas BOL-148 produced mild sedation (P.B. Bradley, 1956). In rabbits, BOL-148 had a neutral effect on eyeblink conditioning, whereas LSD enhances this specific type of behavioral learning (J.A. Harvey, 2003). No affective changes in Papio papio were observed after BOL-148 in doses of 2-4 mg/kg (M.D. Fairchild, 1980).

Table 3 below shows the questionnaire responses for LSD and several LSD derivatives. LSD is the most potent drug, and caused the most positive responses on the questionnaire. BOL-148 is on this table, and at doses of 80 ug/kg, or 50 times the active dose LSD, there were few positive responses on the questionnaire. This shows a lack of effect of BOL-148 as reported by human volunteers.
From other human hallucinogens, LSD derivatives

There is some evidence that BOL-148 pre-treatment protects against LSD psychosis. Studies with rabbits have shown that a dose of 1 mg/kg BOL-148 had no direct temperature effect on rabbits, but prevented the pyretogenic actions of LSD (A. Horita, 1958). In humans, BOL-148 did not function as a direct LSD antagonist since intravenous injections of BOL-148 at the height of a LSD trip did not cancel the LSD effects, but pre-treatment with BOL-148 in nonpsychotic humans did produce tolerance to the LSD reaction, though the tolerance-producing effect of BOL-148 for equal weights of LSD is much less, approximately 1/30 that of LSD and the attenuation of the LSD reaction observed after pre-treatment with BOL-148 is still less than that which occurs after pre-treatment with LSD. (H. Isbell, 1959)

In an experiment with 10 men, pretreatment with BOL-148 for 5 days (1 mg BOL-148 three times daily) significantly attenuated LSD psychosis caused by 0.5-1.5 ug/kg LSD. As shown in the figure below, blood pressure, pupil size and number of positive responses to questionnaire were reduced during LSD challenge 5 days after BOL-148 pretreatment. (Isbell, H. 1959)
From other human hallucinogens, LSD derivatives


Assays that have indicated similarities between LSD and BOL-148 have usually involved samples not involving the whole organism. For example, LSD and BOL-148 were found to have the same affinity for beta-adrenergic receptors (A. Dolphin, 1978), and were equally effective as MAO and acetylcholinesterase inhibitors in histochemical analysis of rat brain (T.R. Shanthaveerappa, 1963).

There is one report from 1957 indicating that BOL-148 may function as a hallucinogen in high doses. Two normal volunteers experienced psychic effects when BOL-148 was administered intravenously to total doses of 18 and 22 mg, or equivalent to ~200 LSD doses.

"In man small doses of bromo-LSD are said to produce none of the bizarre psychic effects noted with LSD but this is not the case when bromo-LSD is administered intravenously in large doses. Thus, when constant intravenous infusions of bromo-LSD were given to normal subjects, both experienced psychic changes, which became more severe as the infusion continued and persisted for 3 to 4 hours after the infusion was stopped. No hallucinations were noted but there were feelings initially of drowsiness, depression, anxiety, and apprehension followed by feelings of irritation, restlessness, and tenseness, and later, intensely disagreeable sensations of unreality and depersonalization, inexplicable feelings of strangeness and mild confusion." (R. Schneckloth, 1957)

Among the LSD analogs, BOL-148 is important because it indicates that substitution at the 2-position can change the activity of the whole molecule. Also, research into BOL-148 has shown that LSD does not induce a psychosis by creating a relative deficiency of 5-HT within the brain. BOL-148 was shown to have more anti-5-HT activity than LSD in vitro and in vivo, thus if LSD worked by blocking 5-HT neurotransmission, BOL-148 would be expected to be a more potent hallucinogenic drug, but BOL-148 is inactive on many accounts.


References

BRADLEY P. B. and A. J. HANCE. (1956). The effects of intraventricular injection of d-lysergic acid diethylamide (LSD 25) and 5-hydroxytryptamine (serotonin) on the electrical activity of the brain of the conscious cat. J.Physiol.
132, 50-1P.

Dolphin, A., A. Enjalbert, J.P. Tassin, M. Lucas and J. Bockaert (1978). Direct interaction of LSD with central "beta"-adrenergic receptors. Life Sci. 22, 345-352.

Eidelberg E., M. Long and M. K. Miller. (1965). Spectrum analysis of EEG changes induced by psychotomimetic agents. Int.J.Neuropharmacol. 4, 255-264.
Fairchild M. D., D. J. Jenden, M. R. Mickey and C. Yale. (1980). EEG effects of hallucinogens and cannabinoids using sleep-waking behavior as baseline. Pharmacol.Biochem.Behav. 12, 99-105.

Harvey J. A. (2003). Role of the serotonin 5-HT(2A) receptor in learning. Learn.Mem. 10, 355-362.

HORITA A. and J. H. GOGERTY. (1958). The pyretogenic effect of 5-hydroxytryptophan and its comparison with that of ISD. J.Pharmacol.Exp.Ther. 122, 195-200.

ISBELL H., E. J. MINER and C. R. LOGAN. (1959). Relationships of psychotomimetic to anti-serotonin potencies of congeners of lysergic acid diethylamide (LSD-25). Psychopharmacologia. 1, 20-28.
ISBELL H., E. J. MINER and C. R. LOGAN. (1959). Cross tolerance between D-2-brom-lysergic acid diethylamide (BOL-148) and the D-diethylamide of lysergic acid (LSD-25). Psychopharmacologia. 1, 109-116.

MONROE R. R. and R. G. HEATH. (1961). Effects of lysergic acid and various derivatives on depth and cortical electrograms. J.Neuropsychiatr. 3, 75-82.

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

Schweigerdt A. K., A. H. Stewart and H. E. Himwich. (1966). An electrographic study of d-lysergic acid diethylamide and nine congeners. J.Pharmacol.Exp.Ther. 151, 353-359.

SHANTHAVEERAPPA, T. R., K. NANDY and G.H. BOURNE (1963). Histochemical studies on the mechanism of action of the hallucinogens D-lysergic acid diethylamide tartrate (lsd-25) and D-2-bromo-lysergic acid tartrate (bol-148) in rat brain. Acta Neuropathol. 3, 29-39.

TURNER W. J. and S. MERLIS. (1958). Chemotherapeutic trials in psychosis. III. 2-Brom-d-lysergic acid diethylamide (BOL 148). Am.J.Psychiatry. 114, 751-752.
Posted by LSD Research at 4:03 AM 2 comments
Labels: 2-position LSD, BOL-148
Wednesday, November 11, 2009
LD50, lethal dose 50
Terrence McKenna explains the concept of LD50.

"We want to take an excursion here and learn a little pharmacology. If you're going to talk about pharmacology, there is one concept that you should get straight, and that's called LD50. It means "lethal dose 50". What does this mean? Well, you have 20 rats and you give them a certain amount of, let's say, mescaline. When half the rats die, that dose, expressed as milligrams per kilogram of body weight, is called the LD50. And when pharmacologists assess the danger in a drug, they ask the following question, "what is the relation of the LD50 to the effective dose?", and if the LD50 of a drug is only 20 times the effective dose, that's considered an incredibly toxic, dangerous, and dubious drug. A good drug is a drug where the LD50 is 200 times more than the effective dose. In the case of LSD, the LD50 for man has never been determined. That's how safe LSD is. We're talking about lethality here, not you know. So people say, "Well are there unsafe psychedelics?" Well, yes, you just look up the LD50s, line them up, and see which ones have the better ratios. By that measurement, by that standard, LSD is the most desirable. But the LD50 of psilocybin is very impressive. You can take 100 times the effective dose of psilocybin and expect to live. Mescaline, not. Mescaline has a bad profile. As an amphetamine, if you took 20 times the effective dose of mescaline, you would probably die. Of course, an effective dose of mescaline is nearly a gram of pure material, 700 milligrams. If you took 20 times 700 milligrams you would be taking nearly 2/3 of an ounce of mescaline..." (Terrence McKenna)

The LD50 of LSD varies from species to species. Rabbit is the most sensitive species known, with LD50 of 0.3 mg/kg i.v. The LD50 for rats is ten times higher at 16.5 mg/kg i.v. Mice tolerate 46-60 mg/kg i.v. LSD (Passie et al, 2008). An intraperitoneal dose of LSD 5.0 mg/kg reportedly caused death in a rat within 30-45 minutes and was associated with cardiac irregularities and general rigidity of musculature (Sylar et al, 1971). A too high dose of LSD typically causes animals to expire by paralysis, bradycardia, or respiratory failure; these effects probably involve centers in the caudal brain stem.

In an experiment with Macacus rhesus, one animal received 240 ug/kg and the other 140 ug/kg, which are enormous doses of LSD. In terms of a 70 kg person, the animals received 168 and 98 hits of LSD. These doses did not produce an excited behavior in monkeys as small doses do, but instead produced sedation. The monkeys became quiet and more sluggish around the cage, and did not jump about the cage as they did before. The monkeys lived.


Reference

Passie, T., J.H. Halpern, D.O. Stichtenoth, H.M. Emrich and A. Hintzen 2008. The pharmacology of lysergic acid diethylamide: A review. CNS Neurosci. Ther. 14, 295-314.

Sklar, S., K.A. Nieforth and M. Malone 1971. Synthesis and preliminary screening of N-ethyltryptamine derivatives related to reserpine and lysergic acid. J. Pharm. Sci. 60, 304-306.

Posted by LSD Research at 8:35 AM 0 comments
Labels: Every chemical has toxicity even water if the dose is too large.
Tuesday, October 13, 2009
Microtubule inhibitors block sense of touch in cockroaches
Microtubules are involved in the sense of touch, vision, and other senses. The cockroach's sense of touch is probably related to the organization of microtubules in its legs.

Mechanical stimulation is sensed by a cockroach through the spines (Campaniform sensilla) on its leg. There is a burst of spikes in the bipolar nerve cell (sensory neuron) associated with the spine, by pressing gently on the mechanoreceptor apparatus in the cockroach leg.


From Microtubules

Colchicine or vinblastine, drugs known to disassemble microtubules, are inferred to disrupt the sense of touch in a cockroach. From 1 to 2 hr after exposure of the leg spine to colchicine or vinblastine, electron microscopy showed no microtubules in the bipolar cell connected to the sensilla, and the typical burst of spikes produced by the tactile probe was replaced by neuronal silence after colchicine drug treatment.

Besides the physical evidence showing microtubule detachment from the basal body in the cockroach spine, there was a change in the electrophysiological response of the bipolar nerve cell after microtubule disruption. These experiments support the hypothesis that sense perception is related to the organization of microtubules in the dendrites of neurons. It is suggested that the proliferation of microtubules in sensory processes may serve to increase the gain of the cell membrane.


Reference

Moran D. T. and F. G. Varela. (1971). Microtubules and sensory transduction. Proc.Natl.Acad.Sci.U.S.A. 68, 757-760. 10.1073/pnas.68.4.757
Posted by LSD Research at 2:12 PM 1 comments
Labels: microtubules
Friday, July 24, 2009
Serotonin-binding protein and LSD
Serotonin-binding protein

A ~50 kDa protein that binds serotonin was first identified in 1974. It was discovered by passing all of the soluble extracts of a cell over a 5-HT affinity column, and then eluting the column with 5-HT. The protein was stored with 5-HT to prevent degradation.

Serotonin-binding protein is expressed in enteric and central serotonergic neurons, including enterochromaffin cells, the nuclei raphe dorsalis, centralis superior, raphe medianus, raphe magnus, raphe obscurus, and raphe pallidus. Also, dense staining with antibodies to serotonin-binding protein was found in the supraependymal plexus lining the ventricular surfaces.


Serotonin-binding protein and LSD

In 1977, Shih and colleagues performed spectroscopic analysis of free LSD and LSD bound to serotonin-binding protein. Free LSD exhibited max fluorescence at 435 nm with excitation at 330 nm, while serotonin-binding-protein-bound-LSD shifted its fluorescence and excitation maximum to 465 nm and 375 nm. These results suggest that the interaction between LSD and serotonin-binding-protein caused a delocalization of the molecular orbital electrons and thereby lengthened the electronic conjugation of the drug molecule.

Figure 2 below shows the excitation (330 nm) and emission (435 nm) wavelengths of free LSD.

From lsd spectroscopy


Figure 3 shows the excitation (375 nm) and emission (465 nm) wavelengths for protein-bound-LSD.

From lsd spectroscopy


An increase in the absorption and emission wavelengths was also observed when bovine serum albumin (BSA) was mixed with LSD, as shown in Figure 4 below. Peak 1 is the fluorescence of BSA. Peak 2 is shifted towards longer wavelengths, and represents the BSA-LSD complex.

From lsd spectroscopy


Generally, a shift of the absorbance towards longer wavelengths can be accomplished by adding Sulfur, Nitrogen, or Oxygen to a molecule, which increases the number of loosely bound electrons. Serotonin-binding-protein and other proteins contains lone pairs of electrons from S, N, and O that can add to the pi-electron system of the LSD molecule, thus modifying its spectra absorbance.


References

Shih J. C. and J. Rho. (1977). The specific interaction between LSD and serotonin-binding protein. Res.Commun.Chem.Pathol.Pharmacol. 16, 637-647.
Posted by LSD Research at 10:25 AM 1 comments
Labels: 5-HT, charge-transfer, delocalized electron
Saturday, June 13, 2009
Qualia of blue
What makes up the qualia of blue? Where does the meaning of blue actually lie? In the rays of blue light itself, or in your interpretation of blue? The fact that we perceive such "things" as blue light or macroscopic objects lying at distinct places is due, partly at least, to the structure of our sensory and intellectual equipment. Even if blue light were abundant in the universe, it would still require a human brain to decode the message of blue light. Whatever we see as "blue" is a construct of the brain, and blue may be merely an interpretation of otherwise white light. In Moby Dick, Melville wrote,

"Consider that the mystical cosmetic which produces every one of her hues, the great principle of light, for ever remains white or colorless in itself, and if operating without medium upon matter, would touch all objects, even tulips and roses, with its own blank tinge-" (H. Melville, 1851)


I love Melville's description of mind as "medium upon matter". Our access to the mystical cosmetic is largely mediated through our senses and other factors.
Posted by LSD Research at 4:56 AM 0 comments
Thursday, June 04, 2009
when kids accidentally ingested LSD
There are reports of autistic or schizophrenic children who have taken LSD in a therapeutic setting, with variable effects. What happens when psychologically normal kids accidentally ingest LSD? Here are 3 anecdotal cases.

CASE 1

In 1966 on a Wednesday morning in April, a 5-year-old girl accidentally ingested 100 ug LSD on a sugar tablet in the refrigerator belonging to her 18-year-old uncle. Her name was Donna, but after the trip she substitutes Deborah for herself Donna, and thought that her body had been torn in half. The story told by the interviewing psychiatrist is very descriptive:

"Within an estimated 15 or 20 minutes the patient began to scream and cry, creating a commotion that awakened the household and alerted the uncle to the mishap. She was alternately screaming and silent. During her quiet periods she was motionless and unresponsive and apparently unaware of her surroundings. Physical examination about three hours after ingestion showed a screaming child with a temperature of 99 F (37 C), a pulse rate of 130 beats per minutes, 30 respirations per minutes, dilated pupils, and hyperreflexia. Treatment consisted of bed-rest and intravenous infusion of saline. Blood cell count and findings from examination of the urine were normal. The serum glutamic oxoloacetic transaminase value was elevated to 82 units and the alkaline phosphatase was elevated to 20.1 units."

"After four or five hours of hospitalization and intermittent napping, the patient became relatively calm, unfrightened, and responsive. At the same time she expressed many bizarre and apparently delusional ideas, such as that her body was cut off at the waist, that she was not herself but was a girl named Dorothy (a name similar to her own, Donna), that it was not she but Dorothy who had eaten supper, that she had gone home and her bed was occupied by a girl named Dorothy. The following morning, after an uneventful night's sleep, she seemed superficially responsive and rational. However, she still maintained that Donna had gone home during the night and that she was Dorothy and she wrote her name as Dorothy. In the course of the morning she became better oriented and began to recognize that she was Donna again."

"Psychiatric examination on the afternoon of April 7, about 30 hours after ingestion, showed a quiet, unreactive, apathetic girl. She responded promptly when questioned, and displayed an alertness that was in marked contrast to her prevailing apathetic mood. Her emotional range was very narrow and lacked normal modulation. Her verbalizations, although brief, were responsive and appropriate and she had a fairly good recollection of the events preceding hospitalization. In contrast to her condition of a few hours earlier, she was oriented and lucid. Her thinking was somewhat concrete. She was not able to express subjective feelings or experiences. It was inferred from her refusal to stand her complaint that her legs "hurt" that she was experiencing either paresthesias or a residuum of the preceding day's profound distortion of body image. She described a dream in which "they stole my mommy and tried to cut her in half" which seemed to be expressing the same distortion of body image or body perception." (D.H. Milman, 1967)

A psychiatric evaluation 5 days later showed that Donna was still abnormal and her IQ had dropped. At evaluation five months later, IQ levels had returned to normal, and the girl had returned completely to her typical behavior with flexible thinking processes. At the final examination nine months after the incident, the patient was in first grade and progressing well. She had a normal IQ, good concentration and cheerful mood with logical and appropriate thinking.

The substitution of her name for Dorothy provides an example of "depersonalization" after LSD, which generally refers to one not being oneself. The description of her body being torn in half suggests that she experienced a major alteration in body image.


CASE #2

A 25-month male infant ingested an estimated 200 ug LSD in the form of 2 purple microdots.

"At 10:30 AM on the day of admission the mother noted the onset of unusual behavior in her child: He appeared unsteady and stumbled, he was frightened and screamed while looking at a colored rug, at the ceiling, or upon seeing a housefly, and he frequently opened his eyes widely and covered his ears with his hands as if to block out unpleasant sounds. The mother recalled she had had two tablets of LSD, purple microdots, in her purse; she found the purse opened and both tablets missing. The child was taken to a local hospital where the family's physician noted that the child was in a state of "stark terror." He clung tightly to his mother, screaming at apparent visual hallucinations perceived on the walls of the examining room; he did not fix his gaze on persons or other objects." (B.M. Ianzito, 1972)

The child received an intramuscular injection of 10 mg chlorpromazine at 12:20 PM, one hour after which he had normal vital signs, was quiet, and fixed his gaze on objects for brief periods. Chlorpromazine seemed to be effective in the case of this 2-year old, although in other subjects chlorpromazine has reportedly intensify the LSD experience.


CASE #3

In 1973, a 23-month male infant admitted to hospital had ingested one LSD tablet 2 hr before admission. The child was very hysterical and hyperreactive. He was given 15 mL ipecac syrup to induce vomiting and he was given water, and a urine sample was collected for spectroscopy analysis. At 3 hours, the patient had calmed down and at 4 hours could recognize his mother. He was sent home from the hospital 2 days later in general good condition.

The dosages of LSD given to these 3 children were well above the adult threshold levels, and there was no indication of brain damage. Screaming and crying seemed to be a common reaction to LSD within the first 2 hours. There was a temperature increase to 99 F in the 5-year-old girl, consistent with an emotionally hyperactive state.


Reference

Ianzito B. M., B. Liskow and M. A. Stewart. (1972). Reaction to LSD in a two-year-old child. J.Pediatr. 80, 643-647. 10.1016/S0022-3476(72)80064-7

Milman D. H. (1967). An untoward reaction to accidental ingestion of LSD in a 5-year-old girl. JAMA. 201, 821-825. 10.1001/jama.201.11.821

Mueller R. G. and G. E. Lang. (1973). Fluorescent spectra of lysergic acid diethylamide: observations on a gastric extract. Am.J.Clin.Pathol. 60, 487-492.
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Saturday, May 23, 2009
LSD dose
The effective dose of LSD varies enormously among species. In salamander, the effective LSD dosage is 700,000 ug/kg. Intracranial injections of 300 ug/kg in goldfish produce the characteristic LSD fish surfacing reaction. In mouse the effective dose is 180 ug/kg of body weight. With LSD behavioral changes are discernible in rat at 80-160 ug/kg but in the cat at 25 ug/kg. A 20 ug/kg LSD affects pigeons' performance in learned discrimination tasks. In rabbit the effective dose is 15 ug/kg. In man, where we have the advantage of verbal reporting, the effective dose is less than 1 ug/kg. According to Albert Hofmann, the effective human dose of LSD is 0.5 ug/kg.

A flat dosage of 100 ug per person is used commonly in human LSD research. This dosage quantity is convenient to remember because it doesn't take body weight in kilograms into consideration. A dosage of 100 ug per person typically results in dramatic symptoms, but the threshold for activity generally is placed at 20 ug LSD per person.

Very low doses of LSD (4-40 ug per person) were tested in human volunteers by Greiner and colleagues in 1958. Psychic changes were established by way of interviews and measurement of pupil size, heart rate, and galvanic skin response. The data below showed that mood and psychomotor effects were detectable in human volunteers at dosages as low as 4 ug LSD per person, which is approximately 0.05 ug/kg of body weight, or 10 times less than the effective dose according to E. Rothlin and Hofmann. The objective measures showed that the galvanic skin response was activated after only 7 ug LSD per person. There was a dose-dependent increase in pupil size, heart rate, and other parameters.

From lsd dose

The researchers observed sudden shifts in affect in the volunteers after 4 ug, 7 ug, or 12 ug of LSD per person, but no significant changes in thought process or content. This data puts the threshold dose for LSD intoxication at about 20 ug per person.

LSD is one of the most potent drugs known to man. Whereas most drugs are administered at doses of tens or hundreds of milligrams, LSD is active at tens or hundreds of micrograms. The potency of LSD is best compared to other drugs on a log scale, as shown in Figure 1 below. It can be seen that the concentration of an active dose of alcohol is about a million times as great, expressed in terms of weight, as the concentration of LSD.

From lsd dose


Of course, the effective dose of LSD depends highly on the person, set, and setting. The dose threshold may be lower for people who are generally inexperienced with drugs, and higher for alcoholics and drug addicts.

“Familiarity with other drugs which produce psychological changes is also relevant. Alcoholics and drug addicts seem better able to cope with the LSD experience than normal subjects. I have had more difficulty with anxiety and panic in normal subjects than in patients who have had long experience with drugs.” (A. Hoffer, 1965)

Fasting or not can change the effective LSD dose too. Plasma concentrations of orally ingested LSD were twice as much on an empty stomach. The amount of the meal as well as the pH of the stomach will influence LSD absorption.


References

GREINER T., N. R. BURCH and R. EDELBERG. (1958). Psychopathology and psychophysiology of minimal LSD-25 dosage; a preliminary dosage-response spectrum. AMA Arch.Neurol.Psychiatry. 79, 208-210.

Passie T., J. H. Halpern, D. O. Stichtenoth, H. M. Emrich and A. Hintzen. (2008). The pharmacology of lysergic Acid diethylamide: a review. CNS Neurosci.Ther. 14, 295-314.
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Labels: Every chemical has toxicity even water if the dose is too large.
Tuesday, April 14, 2009
LSD charge-transfer complexes 3. LSD-riboflavin
Hallucinogenic agents are probably electron donors in some key step involving a charge-transfer complex with a biological acceptor molecule entity. Continuing the discussion of LSD-small molecule complexes, we will see that the same electrostatic and charge-transfer forces in LSD-TCNE, and LSD-NAD+ complexes are present in a LSD-riboflavin complex.

In 1958, Isenberg and Szent-Gyorgyi mixed LSD-25 with riboflavin-5'-phosphate and observed a red color at –78 C. They discovered that the riboflavin molecule had taken up one electron from LSD. These results showed that LSD functions as an electron donor in the formation of riboflavin charge-transfer complexes, and that the transferred electron (e.g. to reduce riboflavin) comes from the pi-electron pool of the LSD indole system. In the same publication, the authors reported on tryptopan-riboflavin, 5-HT-riboflavin, and 1-methyl-medmain-riboflavin complexes, all of which led to the appearance of a red color at -78 C. The results are shown in Table 1 below.

From hallucinogens HOMO, charge-transfer

Histidine-riboflavin or tyrosine-riboflavin did not give a red color, indicating that no charge-transfer complex had been formed, and that histidine and tyrosine are inferior in electron-donating ability compared to drugs such as tryptophan and LSD. There were variations among the drugs which formed a charge-transfer complex with riboflavin. For example, the 5-HT-riboflavin complex was 7X stronger than the tryptophan-riboflavin complex indicating that serotonin was a better electron donor than tryptophan.

The charge-transfer complex formed by flavins with proteins via their tryptophans is of major biological significance. Some tissues such as liver have a great quantity of strongly bound flavin. The brown color of the liver can be attributed to the flavin radical formed in a charge-transfer interaction with liver protein. If liver tissue becomes cancerous, it takes on a different balance of reductive and oxidative processes and changes color.


References

Isenberg I. and A. Szent-Gyorgyi. (1958). FREE RADICAL FORMATION IN RIBOFLAVIN COMPLEXES. Proc.Natl.Acad.Sci.U.S.A. 44, 857-862. doi:10.1073/pnas.44.9.857
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Labels: charge-transfer
Monday, April 13, 2009
LSD charge-transfer complexes 2. LSD-NAD+
The electron acceptor NAD+ forms a charge-transfer complex with LSD, in which an electron is transferred from the highest occupied molecular orbital (HOMO) of the LSD pi system to the lowest empty molecular orbital of NAD+.

The charge-transfer process is accompanied by the appearance of a new absorption band. In 1967, Fulton and colleagues studied the wavelength of the absorption maximum of NAD+ charge-transfer complexes.

“We have shown that NAD+ of concentration 1.03E-2M, when mixed with fairly strong electron donors, such as substituted pteridines, uric acid, serotonin creatine sulphate, lysergic acid, and phenothiazines, gave solutions which were coloured yellow to orange because of the formation of charge-transfer complexes." (A. Fulton, 1967)


Some of the electron donor molecules studied were LSD, indole, uric acid, promazine, and promethazine, and different absorption maximums were obtained for each donor-NAD+ complex as shown in Table 1 below. Also the researchers measured the ionization potential energies of the electron donors, and found that LSD had an ionization potential of 7.8 electron Volts, indole (7.9), uric acid (7.5), promazine (7.2), promethazine (7.2), and chlorpromazine (7.3).

From hallucinogens HOMO, charge-transfer


The authors found that the absorption maximum of the charge-transfer complex correlated reasonably with the ionization potential of the electron donor drug, but not so well with the energies of the HOMO, perhaps because there are many approximations involved in the theoretical studies of the HOMO energy. However other groups have found a correlation between the absorption maximum and kHOMO energies.

As listed in Table 1 above, the LSD-NAD+ charge-transfer complex had an absorption maximum at 340 nm, which is the absorption maximum of the native LSD molecule. This compares to the 520 nm absorption maximum that is characteristic of LSD-TCNE or LSD-Ehrlich complexes.



References

Fulton A. and L. E. Lyons. (1967). Electron-accepting strength of NAD+. Aust.J.Chem. 20, 2267-2268.
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Labels: charge-transfer
Thursday, March 05, 2009
LSD absorption and fluorescence
The LSD molecule contains a number of pi-electrons. These pi-electrons absorb electromagnetic radiation very strongly, like many aromatic or conjugated systems. LSD absorption is maximal at 320 nm, and LSD fluorescence is maximal at 435 nm. These values are somewhat flexible depending on the spectrophotometer, with some authors reporting LSD absorption at 325 nm, and LSD fluorescence at 445 nm. The spectroscopic properties of radioactive [3H]-LSD are the same as LSD, with a maximum fluorescence at 445 nm, and an excitation wavelength of 325 nm. For LSD spotted onto chromatography plates, maximum excitation occurs at 330 nm, and emission at 410 nm. Spots of LSD on thin-layer chromatography plates give a violet-blue fluorescence under a UV lamp.


From lsd spectroscopy

Muller and Lang carefully studied the absorption and fluorescence of LSD as a function of pH. As shown in Figure 1 above, there is a minor excitation peak at 240-250 nm in addition to the major excitation peak of LSD at 330 nm. The major excitation peak of LSD could be shifted by placing the LSD sample in either acid or alkali conditions. The major LSD excitation peak was 327 nm in 0.01 N HCl and 319 nm in 0.05 M Na2HPO4. In basic solution, the 319 nm peak was approximately 25% greater in amplitude than the height of 327 nm in HCl. Major emission peaks of LSD were at 420-430 nm, with a shoulder at 536 nm.

In 1971, in situ fluorometry was performed on LSD using quinine as an internal reference. As seen in the figure below, quinine (A2, B2) and LSD (A1, B1) have the same excitation and fluorescence wavelengths.

From lsd spectroscopy

LSD fluorescence can be used to check its potency. Niwaguchi and colleagues found a linear relationship between fluorescence emission intensity and the amount of LSD on thin-layer chromatograms. If the 9,10 double bond of the D-ring is intact, blue fluorescence is observed under UV lamp.

Since the fluorescence emission intensity is proportional to the amount of LSD, the concentration of an unknown LSD solution can be measured in a Farrand or Bowman spectrophotometer. After blanking with water at 300 nm, solutions of LSD are scanned with 350 to 250 nm light, and the maximum absorbance, which occurs at approximately 330 nm, is compared to a standard solution of LSD. As little as 0.001 microgram of LSD, or 1/100,000 of a dose, can be analyzed this way, thus LSD detected by spectroscopic methods has better sensitivity than LSD detection by coloration with Van Urk reagent.

LSD is among the most fluorescent substances known. LSD is more strongly fluorescent than NN-DMT, diethyltryptamine, psilocybin, or mescaline. For comparison, DMT absorbs at 280 nm, and fluoresces at 350 nm. Psilocybin absorbs at 270 nm and fluoresces at 340 nm.


LSD decomposition

It has been reported that LSD loses its fluorescence very rapidly upon strong ultraviolet irradiation, as shown in the decomposition curves below. After just 5 seconds of irradiation at 320 nm, the LSD fluorescence reading was significantly diminished.

From lsd spectroscopy

If UV irradiation was continued for 15 to 60 minutes, a significant amount of decomposition of LSD was shown by paper chromatography. Only 10% of LSD remained after 60 min UV irradiation while in the control experiment 90% of LSD remained after 17 h standing in the dark.

From lsd spectroscopy

A decrease in LSD fluorescence with irradiation occurs when UV light catalyzes the hydration of LSD to a non-fluorescent derivative. A molecule of water is added across the C9-C10 double bond of LSD to produce the non-fluorescent lumi-derivative. In 1972, Upshall and colleagues described an easy-to-follow procedure for analyzing LSD in human plasma, by measuring the difference in fluorescence (318 nm excitation, 413 nm fluorescence) of plasma extracts before and after intense UV irradiation (at 254 nm). This analytical method (detection of change) is greatly preferable to a direct reading of UV fluorescence in plasma, since the plasma blank reading has sufficient enough magnitude to seriously interfere with the determination of LSD. Upshall determined an average of 1-10 ng LSD per 1 mL human plasma.

From lsd spectroscopy


Upshall's analytical method is superior to spectroscopic techniques that are based on one measurement of LSD fluorescence, because contents of plasma can obscure the native fluorescence of the LSD molecule. When Aghajanian and colleagues measured LSD concentrations in human plasma in 1964, they found a concentration which corresponded to a level of LSD in the plasma that was higher than expected based on a known injection amount. In this case, the contents of plasma may have added to the native fluorescence of the LSD molecule because the researchers obtained a value of 6-7 ng/mL plasma, about 10X higher than expected. The difference in fluorescence of plasma extracts before and after intense UV irradiation is the best way to a measure LSD concentrations in human plasma.


References

AGHAJANIAN G. K. and O. H. BING. (1964). Persistence of Lysergic Acid Diethylamide in the Plasma of Human Subjects. Clin.Pharmacol.Ther. 5, 611-614.

AXELROD J., R. O. BRADY, B. WITKOP and E. V. EVARTS. (1956). Metabolism of lysergic acid diethylamide. Nature. 178, 143-144. 10.1038/178143a0

BOYD E. S. (1958). The fluorometric determination of lysergic acid diethylamide and ergonovine. Arch.Int.Pharmacodyn.Ther. 115, 43-51.

Niwaguchi T. and T. Inoue. (1971). Studies on quantitative in situ fluorometry of lysergic acid diethylamide (LSD) on thin-layer chromatograms. J.Chromatogr. 59, 127-133. 10.1016/S0021-9673(01)80012-1

Sperling A. (1972). Analysis of hallucinogenic drugs. J.Chromatogr.Sci. 10, 268-275.

Upshall D. G. and D. G. Wailling. (1972). The determination of LSD in human plasma following oral administration. Clin.Chim.Acta. 36, 67-73.
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Labels: spectroscopy
Saturday, February 07, 2009
Theoretical studies of the LSD HOMO energy
The highest occupied molecular orbital (HOMO) energies of hallucinogens have been thoroughly investigated, experimentally as well as theoretically. There is a direct relationship between molecular orbital parameters and hallucinogenicity. It is well-known that hallucinogen dose is correlated with the affinity to 5-HT receptors, but within this index are other relationships more directly related, in this case, the HOMO energy of the hallucinogen molecule. Receptor affinities reflect the likelihood of formation of a charge-transfer complex between drug and receptor, and these charge-transfer energies are directly related to the HOMO energy of electron donor molecules, or in this case, hallucinogen molecules. Other factors such as hydrophobicity and steric factors are incorporated within the index of receptor binding as well, but some minimum level of HOMO energy is necessary for hallucinogenic activity. Here is a chronological review of the research on HOMO energies of hallucinogen molecules.

In 1965, Snyder and colleagues calculated the HOMO energies of several hallucinogens using the Huckel method. Table 4 below lists the HOMO energy for LSD, psilocin, and TMA-2. The authors used the value (HOMO=0.218) obtained by Karreman and Szent-Gyorgyi for the LSD HOMO energy.





From hallucinogens HOMO LEMO


Psilocin, LSD, TMA-2, and TMA had a more energetic HOMO compared to the non-hallucinogenic drugs tyramine, dopamine, and phenyethylamine. Snyder and colleagues concluded that there is a relationship between hallucinogenic activity and the ability to donate electrons, as indicated by the energy of the HOMOs.

In 1968, Millie and colleagues investigated the HOMO energy of 1-methyl-LSD. They report Ehomo=0.487 for 1-methyl-LSD, thus placing 1-methyl-LSD somewhere in between 4-methoxy-indole and 5-methoxy-indole in terms of its electron donor ability. To my knowledge, Millie, Kang and Green, and Karreman and Szent-Gyorgyi are the only authors that have calculated the Ehomo for LSD-type molecules.

In 1970, Kang and Green calculated the HOMO energy of 13 psychotomimetic amphetamines, using the INDO (intermediate neglect of differential overlap) method, which is superior to the Huckel method. Table I lists the HOMO energy, Eh, of the hallucinogenic amphetamines. The most potent drugs had a smaller Eh value. There was a linear correlation between Eh and hallucinogenic activity in man.





From hallucinogens HOMO LEMO

Kang and Green also reported the Ehomo value for N,N-DMT and LSD, in Table 1 (below).





From hallucinogens HOMO, charge-transfer


In Kang and Green's research, the compound 4-hydroxy-N,N-DMT (psilocin, Eh=-0.4493) was predicted to be more potent than LSD (Eh=-0.4745) going by Eh value alone, but overall, these authors were successful at correlating the actions of hallucinogens agents with Huckel molecular orbital calculations.

In 1971, Nieforth wrote a review about HOMO energy and hallucinogens, which copied Snyder's 1965 data.





From hallucinogens HOMO LEMO


Nieforth concluded that electronic energy parameters were not the only factor involved in the biological activity of hallucinogens, since other compounds such as chlorpromazine are powerful electron donors and do not possess hallucinogenic activity. (5)

By 1979, another review on hallucinogen HOMO energies appeared, which reproduced Snyder's 1965 data yet again.





From hallucinogens HOMO LEMO


Gupta verified the conclusion that there is a highly significant correlation between Ehomo and hallucinogenic activity, but he suggested that a charge-transfer phenomenon may not be the only factor responsible for the biological activity of the drugs. According to Gupta, the theory of charge-transfer formation does not fully explain drug potency in the case of anesthetic drugs.

By 1987, another review summarized the charge-transfer complexes of receptors with hallucinogens.

“In hallucinogens the electron transfer is considered to be an outer-sphere, charge-transfer process. An overall electrostatic interaction with the receptor is envisioned as a result of the charge transfer from the aromatic portion of hallucinogens to their putative receptors. .. The hallucinogenic activity of phenyl alkyl amines, indole alkl amines, and LSD was first linked to the electron transfer ability of these drugs almost three decades ago. Huckel molecular orbital calculations of a series of hallucinogenic drugs and their nonhallucinogenic structural analogues indicated the close relationship between the HOMO energy, an index of electron-donating ability, and the hallucinogenic potency. Based on these results, an electron donation model of interaction between hallucinogenic drugs and their putative receptors was proposed. Later, a series of more sophisticated molecular orbital calculations confirmed the trends initially observed with the simple Huckel method. The HOMO energies of hallucinogens were also assessed experimentally, via measurements of ionization potentials and charge-transfer capabilities of these drugs. A good agreement was obtained between the calculated and the experimentally-deduced HOMO energies.” (Kolb,V.M., 1987)

The HOMO energy, which is an index of electron-donating ability of a molecule, has been studied because of its relation to the threshold dose of hallucinogen drugs. The HOMO energy reflects the compounds’ ability to donate electrons in a charge-transfer type of interaction, thus molecular orbital calculations of hallucinogen molecules support a charge-transfer mechanism of action of hallucinogenic drugs.


References

1. Snyder S. H. and C. R. Merril. (1965). A relationship between the hallucinogenic activity of drugs and their electronic configuration. Proc.Natl.Acad.Sci.U.S.A. 54, 258-266. doi:10.1073/pnas.54.1.258

2. Millie P., J. P. Malrieu, J. Benaim, J. Y. Lallemand and M. Julia. (1968). Researches in the indole series. XX. Quantum mechanical calculations and charge-transfer complexes of substituted indoles. J.Med.Chem. 11, 207-211. doi:10.1021/jm00308a003

3. Kang S. and J. P. Green. (1970). Steric and electronic relationships among some hallucinogenic compounds. Proc.Natl.Acad.Sci.U.S.A. 67, 62-67. doi:10.1073/pnas.67.1.62

4. Kang S. and J. P. Green. (1970). Correlation between activity and electronic state of hallucinogenic amphetamines. Nature. 226, 645.

5. Nieforth K. A. (1971). Psychotomimetic phenethylamines. J.Pharm.Sci. 60, 655-665. doi:10.1002/jps.2600600502

6. Kolb V. M. (1987). Electron-transfer and charge-transfer clastic binding hypotheses for drug-receptor interactions. Pharm.Res. 4, 450-456. doi:10.1023/A:1016415202819


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Labels: molecular orbital theory
Wednesday, February 04, 2009
Indole charge-transfer complexes
What is a charge-transfer complex? There is a electron donor and electron acceptor molecule. The electron donor possesses a weakly bound electron or pair of electrons, and the electron acceptor has vacant orbitals. When a single electron participates in the transfer, the transferred electron goes from the highest filled orbital of the donor to the lowest empty orbital of the acceptor. The resulting charge-transfer complex can be a strikingly different color than the reagents.

5-HT is an exceptional electron donor. It tends to have the effect of shifting the outer shell electrons from one molecule to another, thus 5-HT has the propensity to form donor-acceptor complexes with electron acceptors such as picric acid. In the formation of serotonin-picrate crystals, serotonin is the donor molecule and picrate is the electron acceptor. A red-colored charge-transfer complex is formed when serotonin is added to picric acid.

The geometry of charge-transfer electronic transitions has been studied with crystal structures of serotonin-picrate. In serotonin-picrate crystals, the nitro groups of picric acid interact with C2 and C3 of the indole ring, suggesting that the nitro group of the electron acceptor associates with the pi electron cloud of 5-HT.

"It is significant that the observed geometry is such that charge-transfer electronic transitions apparently can occur and impart color to the [red serotonin picrate] crystals." (C.E. Bugg, 1970)

Indoles in general form charge-transfer complexes. The exceptional electron-donating ability of the indole nucleus is related to a high-lying pi electron on the carbon atom at position-3 of the indole donor. Serotonin, tryptophan, aminotryptophan, and methoxytryptophan all function as electron donor molecules in the formation of charge-transfer complexes. These indole donors can pair with electron acceptor molecules of biological importance, such as riboflavin, nicotinamide, or DPN.

Tryptophan is an indole derivative, and it is a better electron donor than most aromatic amino acids, thus proteins are known to participate in charge-transfer reactions via their tryptophan residues. When tryptophan is mixed with riboflavin, and cooled to -78 C, a strong red color is observed. Tryptophan also forms a visible charge-transfer complex with electron acceptors DPN+ or TPN+. At the temperature of dry ice, tryptophan-DPN+ and tryptophan-TPN+ complexes had a yellow color, with strong absorption in the region of 400 nm.

Overall, serotonin is a better electron donor than tryptophan. This has been shown theoretically by calculating the kHOMO energy of 5-HT and tryptophan, and experimentally by mixing 5-HT or tryptophan with the same electron acceptor, riboflavin. 5-HT and tryptophan both form charge-transfer complexes with riboflavin but serotonin complexes much more strongly, thus it has been verified that serotonin is a better electron donor than tryptophan. The physiological properties of 5-HT might be related to the exceptional electron donor capabilities of the hydroxyindole moiety.

Coming to the present topic, LSD is an extremely good electron donor with kHOMO=0.218-0.487, which has been shown to form charge-transfer complexes with the small molecules such as riboflavin, TCNE, and dimethylaminobenzaldehyde. Also, LSD forms charge-transfer complexes with electron acceptor macromolecules, such as wool protein, dopamine receptors, and 5-HT2A receptors. It has long been suspected that psychoactive drugs, including chlorpromazine and phenothiazine derivatives, function as electron donors in a key step involving charge-transfer interactions. Drugs may donate or accept electrons, disrupting the normal pathway for electron transport and thus interfering with oxidation-reduction processes such as the respiration chain.



References

Bugg C. E. and U. Thewalt. (1970). Crystal structure of serotonin picrate, a donor-acceptor complex. Science. 170, 852-854. 10.1126/science.170.3960.852
Isenberg I. and A. Szent-Gyorgyi. (1959). On Charge Transfer Complexes between Substances of Biochemical Interest. Proc.Natl.Acad.Sci.U.S.A. 45, 1229-1231. 10.1073/pnas.45.8.1229

SZENT-GYORGYI A., I. ISENBERG and J. McLAUGHLIN. (1961). Local and pi-pi interactions in charge transfer. Proc.Natl.Acad.Sci.U.S.A. 47, 1089-1094. 10.1073/pnas.47.8.1089
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Labels: 5-HT, charge-transfer
Wednesday, January 14, 2009
Ergotamine mysteries
LSD is related to ergotamine. There are many unsolved mysteries related to ergotamine chemistry.

Two and a half millennia ago, Grecians celebrated Demeter by drinking kykeon, a drink made from fermented barley water. This special drink contained ergotamine and caused in participants intensive psychic changes, which cleared their souls, and made them accept death not so much as harm as a blessing, as one of the ancient diarists reported. Kykeon was consumed on a 14 mile walk from Athens to Eleusis, which culminated in a mysterious all-night ceremony. The site of Eleusis was burned by a Christian barbarian, according to Terrence McKenna.

Ergot is the name given to the dark-colored fungus growing on pods of rye (below). It is a horn-shaped growth that is typically in the neighborhood of 10 to 15 mm long, and can reach diameters of about 5 mm. The ergot consists of tightly interwoven hyphae of fungus. The ergotamine-containing fungus is named Claviceps purpurea.

From LSD research


Breads made from contaminated grains may have led to bizarre events in history such as the Salem Witch Trials in 1692. Around 1830, in rural areas of Germany, the scientist Karl von Reichenbach built a special conservatory for studying "sensitive" individuals, and he refracted moonbeams into the room for their amusement. Presumably, von Reichenbach's "sensitives" were patients who had consumed ergotamine from contaminated bread crops.

Posted by LSD Research at 6:19 AM
Monday, January 05, 2009
LSD exhibits a low transport number in glass pipettes
The ionotophoretic method for the application of drugs from micropipettes is important for the good spatial and temporal resolution which it offers. With ionotophoretic methods, drugs can be applied to single neurons in a specific area of the brain. Ionotophoretic experiments significantly change the natural chemical environment of a neuron, yet the effects of drugs on neuron spiking are frequently assessed with ionotophoresis.

A iontophoretic pipette is a thin metal wire in a glass cylinder, that is filled with a solution of drug. A "retaining" current is passed through the micropipette via the wire to suppress the spontaneous release of drug. A large retaining current will greatly depress the release of drug from the pipette tip, although no value of retaining current will prevent completely the diffusional efflux of drug from the ionotophoretic pipette. When the pipette is in place and the experimenter is ready to release the drug, an "ejection" current is applied. This stimulus is applied as a brief current pulse, not a steady current. There is a theoretical relationship between the ejection current and release of drug ions. The drug solution will be expelled from the tip of the pipette, depending on the amount of current passed and the drug's "transport number," which is the ratio of drug released to charge passed.

LSD has an exceptionally low transport number (t=0.02) for a chemical substance, thus very long periods of iontophoresis must be used for LSD. Most of the LSD molecules tend to stay in the pipette, even with large ejection currents. In comparison, acetylcholine and 5-HT have high transport numbers (t=0.2-0.4), and require short bursts of current to be released from the pipette.

When dealing with iontophoretic release of drugs from pipettes, we usually want to know the amount of drug released, but the value known with confidence is the ejection current. To calculate the transport number of each drug, the electrophysiologist must use pipettes that are filled with a radioactive isotope of the drug, and different ejection currents. Then, the electrical charge (ucoulomb) in the pipette is plotted versus iontophoretic release (pmol) of [3H]-LSD, as shown in the figure below. LSD-25 release from pipettes was directly proportional to the charge passed through the pipette. The transport number of LSD was obtained from this data by multiplying the slope (expressed in mol/coulomb) by Faraday's number.

From lsd transport number

In 1974, Haigler and colleagues reported that the transport number of LSD (0.0023) was much smaller than 5-HT (0.219). According to these researchers, 100 nA of ejection current of LSD would be equivalent to 1 nA ejection current of 5-HT in terms of the number of drug molecules ejected.

“since equal currents of both agents inhibit the raphe, LSD emerges as being more potent than 5-HT, molecule for molecule, on the raphe neurons." (H.J. Haigler, 1974)

Some researchers found it difficult to pass current through LSD-containing glass electrodes.

“It was often impossible to pass current through barrels containing 2% LSD 25 solution for long periods. Longer applications of LSD 25 from a 0.5% solution had a depressant action on 22 out of 35 neurons tested.” (Boakes,R.J., 1970)

Chlorpromazine and Levallorphan, a drug similar to naloxone, have low transport numbers too. The transport numbers of chlorpromazine and Levallorphan are 0.0858 and 0.0737.

A molecule's transport number is easy to measure, and it gives information about the electronic properties of a drug. There was more similarity between chlorpromazine and LSD than LSD and 5-HT. The similarity of physical properties of chlorpromazine and LSD may be due to more conjugation of the rings compared to 5-HT molecules.

Reference

Boakes R. J., P. B. Bradley, I. Briggs and A. Dray. (1970). Antagonism of 5-hydroxytryptamine by LSD 25 in the central nervous system: a possible neuronal basis for the actions of LSD 25. Br.J.Pharmacol. 40, 202-218.

Bradley P. B. and J. M. Candy. (1970). Iontophoretic release of acetylcholine, noradrenaline, 5-hydroxytryptamine and D-lysergic acid diethylamide from micropipettes. Br.J.Pharmacol. 40, 194-201.

Haigler H. J. and G. K. Aghajanian. (1974). Lysergic acid diethylamide and serotonin: a comparison of effects on serotonergic neurons and neurons receiving a serotonergic input. J.Pharmacol.Exp.Ther. 188, 688-699.
Zieglgansberger W., G. Sothmann and A. Herz. (1974). Iontophoretic release of substances from micropipettes in vitro. Neuropharmacology. 13, 417-422. 10.1016/0028-3908(74)90129-4
Posted by LSD Research at 1:13 PM 0 comments
Labels: transport number
Sunday, December 21, 2008
LSD chromatography
The formation of a charge-transfer complex is accompanied by the appearance of a new color band. Histologists have long been interested in charge-transfer reactions for developing staining procedures based on the appearance of a visible color. For example, Romanowsky-Giemsa staining is due to azure B and eosin Y molecules, which act as electron acceptor and donor in the formation of a purple-colored charge-transfer complex.

Electron acceptor reagents have been used as color test reagents for the detection of hallucinogenic drugs. This was shown in 1973, when twenty different hallucinogens were applied to chromatography plates and then sprayed with one of various chromogenic reagents. The formation of a color band was dependent on the electron-donating properties of the drug molecule.

“As would have been expected, the polycyclic and consequently more “electron-rich” hallucinogens, such as the harmine derivatives gave stronger colors than the simple monocyclic beta-phenylethylamines derivatives such as mescaline, TMA, DOM, or 2,3-dimethoxy-amphetamine,” (R.A. Heacock, 1973)

The tryptamine derivatives DMT, methyltryptamine, and alpha-methyltryptamine reacted strongly with tetracyanoethylene (TCNE), an electron acceptor. Beta-carboline derivatives 6-methoxyharmalan and harmaline gave intense colors with TCNE and all electron acceptors studied. Ibogaine and LSD were easily detected with TCNE. The chromatographic evidence suggests that the broadly defined class of hallucinogens function as electron donors, because one of the most characteristic evidence for a charge-transfer process is the appearance of a new absorption band.

Erspamer was the first scientist to study enteramine (serotonin) in depth. His technique involved staining with the Ehrlich reaction to test for the presence of serotonin. Also referred to as Van Urk's reagent, Ehrlich's reagent is 2% dimethylaminobenzaldehyde in hydrochloric acid, and forms a purple charge-transfer complex with serotonin as well as most indoles, LSD and chlorpromazine. A purple charge-transfer complex is formed when Ehrlich's reagent is mixed with LSD. According to Hofmann, psilocybin gave a violet color characteristic of indoles in Van Urk reactions.

From lsd spectroscopy


The LSD-Van Urk complex produces an absorption band at 520 nm. Chlorpromazine can be detected by Van Urk reagent, giving an absorption peak at 520 nm. As predicted by its HOMO energy, chlorpromazine is an excellent electron donor, so it is not surprising that chlorpromazine would form a charge-transfer reactions with the electron acceptor Van Urk reagent.

"The procedure allows for a simple, rapid, and accurate determination of small quantities of chlorpromazine." (B.S. Murty, 1970)

Chlorpromazine is considered to be an antipsychotic drug and LSD is considered to be one of the most powerful hallucinogen drugs known to man, and there are many electronic similarities between LSD and chlorpromazine. LSD and chlorpromazine both have a low transport number, and they both react with Van Urk reagent to produce a macromolecular complex with an absorption peak at 520 nm. The similarites between LSD and chlorpromazine could be related to their common anthracene-like structure, known to have exceptional electron-donating and electron-receiving properties.


Reference

Heacock R. A. and J. E. Forrest. (1973). The use of electron-acceptor reagents for the detection of some hallucinogens. J.Chromatogr. 78, 240-250. 10.1016/S0021-9673(01)99063-6

HOFMANN A. (1961). Chemical pharmacological and medical aspects of psychotomimetics. J.Exp.Med.Sci. 5, 31-51.

Murty B. S. and R. M. Baxter. (1970). Spectrophotometric determination of chlorpromazine in pharmaceutical dosage forms. J.Pharm.Sci. 59, 1010-1011. 10.1002/jps.2600590721

Posted by LSD Research at 11:54 AM 0 comments
Labels: charge-transfer
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Basically, mental experiences are drug-induced experiences, whether they are endogenous produced compounds or exogenous compounds.