D-lysergic Acid Diethylamide Research Articles

Acute psychosis induced by psychotomimetic drug abuse. II. Neurochemical findings.

Following probenecid administration lumbar cerebrospinal fluid 5hydroxyindoleacetic acid (5HIAA) and homovanillic acid (HVA) were measured before and during phenothiazine treatment in 12 patients who developed psychotic episodes following the ingestion of a psychotomimetic drug, probably D-lysergic acid diethylamide (LSD-25) in all but two cases. Compared to nondrug-induced psychotic patients and inmate controls the drug-induced patients gave evidence of decreased central 5HIAA formation, findings analagous to those obtained following the administration of LSD-like drugs to animals. These results persisted during phenothiazine treatment.

The influence of D-lysergic acid diethylamide (LSD) on the response properties of cells in the cat lateral geniculate nucleus: G. Horn and J. McKay — Department of Anatomy, University of Cambridge, Cambridge (Great Britain)

The influence of D-lysergic acid diethylamide (LSD) on the response properties of cells in the cat lateral geniculate nucleus: G. Horn and J. McKay — Department of Anatomy, University of Cambridge, Cambridge (Great Britain)

Binding of d-lysergic acid diethylamide to subcellular fractions from rat brain.

WE have examined some of the characteristics of LSD (d-lysergic acid diethylamide) binding to subcellular fractions from rat brain, on the assumption that whatever the mode of action of LSD may be, the drug must first bind to LSD receptors. Studies on a model LSD receptor, that is, the receptor site of an antibody to d-lysergamide, have already been described1.

Interaction of some centrally active drugs with caeruloplasmin

Centrally active drugs such as D-lysergic acid diethylamide (LSD), and to a lesser extent ibogaine and 2-bromo-LSD, are shown to inhibit the caeruloplasmin-catalysed oxidation of 5-hydroxytryptamine but accelerate the oxidation of noradrenaline and dopamine. Harmine and harmol inhibit the enzymic oxidation of all three substrates. Centrally active anticholinergics and substituted phenylethylamines do not affect the enzymic oxidation of these substrates. Some drugs used in the treatment of mental illness affect the caeruloplasmin-catalysed oxidation of noradrenaline, dopamine and 5-hydroxytryptamine. Tranquillizers of the phenothiazine class, for example, accelerate the oxidation of all three substrates whilst antidepressant drugs (other than monoamine oxidase inhibitors) inhibit the oxidation of all three substrates. The results obtained show that caeruloplasmin cannot be generally used as a model for those receptors with which some centrally active drugs must interact to produce their characteristic effects; they do, however, suggest that caeruloplasmin, or an enzyme with similar properties, may be of importance in controlling the relative concentrations of noradrenaline, dopamine and 5-hydroxytryptamine in those areas of the brain where these compounds act as neuro-transmitters.

The Actions of Drugs on Single Neurones in the Brain

Publisher Summary The technique of microiontophoresis, which enables pharmacologically active substances to be ejected from micropipettes in the vicinity of single neurones, can be used not only for studying the actions of putative transmitter substances in the CNS, but also to examine the effects of centrally acting drugs at the neuronal level, and in particular, to determine whether such drugs mimic or interfere with the actions of synaptic transmitters. Using unanaesthetised decerebrate cats, this chapter studies the effects of iontophoretically applied acetylcholine (ACh), noradrenaline (NA) and 5-hydroxytryptamine (5-HT), and other substances, on the activity of single neurones in the brain stem reticular formation. The effects of three centrally acting drugs and their interactions with these three neurotransmitters are studied here. The second centrally acting drug to be studied is D-lysergic acid diethylamide (LSD-25). In 1953, Gaddum proposed that, since LSD-25 is a potent antagonist to 5-HT peripherally, a similar action in the central nervous system might explain the psychotomimetic effects of this substance. Against this suggestion was the finding that Brom-LSD (BOL-I48), which is without psychotomimetic actions, is just as potent as a 5-HT antagonist. The effects of iontophoretically applied LSD-25, and two related substances, BOL-148 and methysergide (UML), are therefore examined in relation to the actions of ACh, NA and 5-HT on brain stem neurones. Certain excitatory and inhibitory amino acids are also included in this study.

Optical activity of LSD-DNA mixtures.

REPORTS on the fluorescence-sensitive binding of d-LSD (d-lysergic acid diethylamide), 1-LSD and their 2-bromo derivatives to calf thymus DNA1, and on changes induced in DNA circular dichroism by LDS-25 (ref. 2), have led to the belief that it is the intercalation of the drug in DNA that causes the chromosomal damage3–6 and abnormalities in human offspring7 that have been associated with LSD. Our studies of circular dichroism, however, have failed to show that LSD has any effect on DNA conformation.

Effect of N,N-dimethyltryptamine and D-lysergic acid diethylamide on the release of 5-hydroxyindoles in rat forebrain.

SEVERAL investigators have already shown that electrical stimulation of the mid-brain raphe, in which neuronal perikarya containing 5-hydroxytryptamine (serotonin) are almost exclusively located1, produces a significant increase in the forebrain content of 5-hydroxyindolyl-3-acetic acid (5-HIAA), while the concentration of serotonin decreased or remained unchanged2–6. This communication describes how N,N-dimethyltryptamine (DMT) and D-lysergic acid diethylamide (LSD), the two potent psychotogenic drugs, affect the release of serotonin and 5-HIAA in the forebrain when the mid-brain is stimulated. Both drugs uniformly inhibit the response of single units in the mid-brain raphe nuclei7,8.

Behavioural and electrographic effects of d-lysergic acid diethylamide (LSD 25) on the photosensitive Papio papio

The behaviour, spontaneous electrographic activities, the visual evoked potential and the photosensitivity of fifteen Papio papio were studied before and after intravenous administration of LSD 25. The changes in these different parameters were noted and the possible relationships between them were investigated. 1. 1. The changes in behaviour appeared earlier and at a lower threshold in animals fixed in special chairs than in animals at liberty. They were of three kinds, involving vision, the somatomotor and autonomic systems. Return to normal behaviour occurred rapidly after small doses but progressively and more slowly after increased doses. 2. 2. The electrographic changes were reproducible from one animal to another, appearing very rapidly and being the last to disappear. They consisted mainly in an increase of frequency and decrease of amplitude, as well as blocking of the spontaneous paroxysmal components. 3. 3. Average evoked potentials recorded from the retina and the optic tract were not decreased in amplitude whatever the dose. On the other hand, with small doses of the order of 0.5 gamma/kg, LSD 25 always depressed synaptic transmission in the lateral geniculate body, for a time depending on the dose. In the occipital cortex the average visual evoked potential was also modified by very small doses: the early wave II decreased in amplitude and could even disappear completely, while the amplitude of wave III persistently increased. At the same time the irradiation of the visual evoked response to the fronto-rolandic cortex was blocked. 4. 4. Above 20–30 gamma/kg LSD more or less completely blocked the paroxysmal electroclinical discharges which are usually produced by photic stimulation in the photosensitive Papio papio. The length of protection varied according to the dose. 5. 5. There was a strict correlation between the disturbances of behaviour (refusal of food), the disappearance of photosensitivity, the decrease in amplitude of the early wave of the visual evoked potential in the lateral geniculate body and the occipital cortex, the increase in the late wave of the occipital evoked potential and the blocking of the irradiated fronto-rolandic response. The photosensitivity of Papio papio thus seems to require the integrity of the occipital evoked potential (primary of the early wave, secondarily of the late wave) and the arrival of impulses in the fronto-rolandic region.

Acquisition of conditioned avoidance response in rats under the influence of addicting drugs.

Four groups of white rats, aged 8–12 weeks, were treated with morphine, d-lysergic acid diethylamide, dl-amphetamine and ethanol, respectively, while being trained in a conditioned avoidance response (CAR) schedule. Morphine caused deterioration in the acquisition of CAR, as manifested by significant increases in the number of training sessions required for 100% correct CAR and in the reaction time (RT), when compared to those of a control group. The RT decreased after withdrawal of morphine and was associated with a revival of the conditioned emotional responses (CER). LSD and ethanol insignificantly retarded the acquisition of CAR, while withdrawal of LSD caused significant increases in the RT, error and CER. Amphetamine facilitated the acquisition rate associated with increased CER; during withdrawal, the CER was negligible whereas the error increased significantly. In another series of rats, tolerance was seen to morphine and, to a less extent, to ethanol and amphetamine after 8–12 days of continued treatment; whereas the withdrawal effects lasted for 3–4 days only. These effects of the addicting drugs on conditioned learning are discussed in the light of their influence on the emotional responses of the animals and the degree of development of drug-dependence.

Studies on Lysergic Acid Diethylamide and Related Compounds. I. Synthesis of d-N<SUP>6</SUP>-Demethyl-lysergic Acid Diethylamide

d-N6-Demethyl lysergic acid diethlyamide (V) was synthesized by the following procedures. von Braun reaction of d-lysergic acid diethylamide (LSD) (I) gave d-N6-cyano-N6-demethyl LSD (II), followed by alkaline hydrolysis in dioxane to give mainly urea type compound (IV) together with a trace of V. The conversion of IV to V was achieved by treatment with sodium nitrite and tartaric acid. On the other hand, alkaline hydrolysis of II in MeOH gave isourea type compound (VI) and a small amount of V.

LSD revisited. A ten-year follow-up of medical LSD use.

A follow-up survey of 247 persons who received d-lysergic acid diethylamide (LSD) in either an experimental (nonmedical) or Psychotherapeutic setting was made to determine the lasting effects, if any, related to use of the drug. Information was collected from each by a structured interview and self-administered questionnaire. Some subsequent nonmedical use of LSD was reported by 23%, who attributed more personality changes to the drug's use. There is, however, little evidence that measurable, lasting personality, belief, value, attitude, or behavior changes were produced in the sample as a whole. Compulsive patterns of LSD use rarely developed; the nature of the drug effect apparently is such that it becomes less attractive with continued use and, in the long-term, is almost always self-limiting.

Necrotizing angiitis associated with drug abuse.

Fourteen young drug abusers with a necrotizing angiitis indistinguishable from periarteritis nodosa were studied. The six women and eight men had used narcotics, stimulants, hallucinogens and depressants. Methamphetamine, alone or in combination with heroin or d-lysergic acid diethylamide, was used commonly. The clinical presentation varied from a complete lack of symptoms in five patients to pleomorphic systemic signs and symptoms with renal failure, hypertension, pulmonary edema and pancreatitis. The vascular changes of necrotizing angiitis, including arterial aneurysms and sacculations, were noted in the kidney, liver, pancreas and small bowel at selective angiography. Post-mortem findings in four patients revealed generalized vascular changes of differing age, including chronic and healed lesions. Because of the multiplicity of injected substances with the high probability of contamination the exact etiologic agent in these cases is not clear; however, methamphetamine appears to be a common denominator.

Iontophoretic release of acetylcholine, noradrenaline, 5-hydroxytryptamine and D-lysergic acid diethylamide from micropipettes.

1. The in vitro iontophoretic release of tritium-labelled acetylcholine and 5-hydroxytryptamine from large and small micropipettes and noradrenaline and D-lysergic acid diethylamide from small micropipettes was determined by liquid scintillation counting.2. The release was directly proportional to the electrical charge passed in the range normally used in the iontophoretic study of these compounds. The transport numbers obtained for the large micropipettes were approximately double those with the small micropipettes. A very low transport number was found for D-lysergic acid diethylamide.3. The spontaneous leakage was small and did not vary appreciably with time.4. The iontophoretic release of acetylcholine in vitro agreed with the in vitro measurements.5. The brain-stem tissue concentration of D-lysergic acid diethylamide after intravenous injection into intact and decerebrate cats was determined.

Antagonism of 5-hydroxytryptamine by LSD 25 in the central nervous system: a possible neuronal basis for the actions of LSD 25.

1. 5-Hydroxytryptamine (5-HT), acetylcholine (ACh), noradrenaline (NA), glutamate, D,L-homocysteic acid (DLH), glycine and gamma-aminobutyric acid (GABA) were applied to single neurones in the brain stem of decerebrate cats by microiontophoresis. The abilities of D-lysergic acid diethylamide tartrate (LSD 25), methysergide maleate (UML 491) and 2-bromo-lysergic acid diethylamide (BOL 148) to antagonize the actions of these compounds were studied.2. LSD 25 antagonized 5-HT excitation of single neurones when applied iontophoretically or administered intravenously. LSD 25 also antagonized glutamate excitation of neurones which could be excited by 5-HT. Inhibitory effects of 5-HT, the action of glutamate on neurones which could be inhibited by 5-HT and the actions of all the other compounds tested were unaffected by LSD 25.3. Iontophoretically applied UML 491 was also a specific antagonist to 5-HT and glutamate excitation but was less potent than LSD 25, and BOL 148 rarely exhibited antagonism.4. It is suggested that antagonism to 5-HT and glutamate excitation of brain stem neurones may be the basis of the psychotomimetic action of LSD 25. It is also suggested that there may be similarities in the mechanisms by which 5-HT and glutamate produce excitation where they act on the same neurone.

Steric and electronic relationships among some hallucinogenic compounds.

Stereochemical considerations and total valence electron calculations suggest congruities among the ostensibly dissimilar hallucinogenic compounds, D-lysergic acid diethylamide (LSD), indolcalkylamines, and methoxylated amphetamines. In LSD the aromatic benzene ring A and the N-6 nitrogen are essential for hallucinogenic activity; these sites may react with the receptor. The conformations of amphetamines and indolealkylamines at the receptor are such that the aromatic benzene ring lies like ring A of LSD and the alkylamino nitrogen lies like the N-6 of LSD. Ring A may interact with the receptor by forming a pi-molecular complex, as suggested by the correlation between hallucinogenic activity and energy of the highest occupied molecular orbital (E(H)) of congeneric series. The N-6 nitrogen of LSD and the sterically congruent nitrogen of the other hallucinogenic compounds may react with the receptor by forming a donor acceptor complex of the n-pi(*) or n-sigma(*) type. Other portions of the hallucinogenic molecules confer a favorable E(H): these include the methoxy and hydroxyl groups of the amphetamines (and mescaline), and the indolealkylamines; and the pyrrole ring of LSD and the indolealkylamines.

Chromosome studies on patients (in vivo) and cells (in vitro) treated with lysergic acid diethylamide.

In a prospective study of 10 patients given d-lysergic acid diethylamide 25, there was no difference in frequency of chromosome breakage between samples obtained immediately before and 24 hours after treatment. In 11 patients, treated over periods ranging from 24 hours to eight years before sampling, the frequency of chromosomal breaks did not differ from that found in untreated controls. In an in vitro study the frequency of chromosomal breaks was increased in replicate cultures from each of 10 subjects when 1 μg per milliliter of d-lysergic acid diethylamide 25 was added during the last 24 hours of culture. There is no cytogenetic evidence that d-lysergic acid diethylamide 25 given therapeutically produces chromosomal damage. The chromosomal aberrations found after illicit use of the drug remain unexplained.

Lysergic acid diethylamide: role in conversion of plasma tryptophan to brain serotonin (5-hydroxytryptamine).

Injections of D-lysergic acid diethylamide decrease the turnover rate of 5-hydroxytryptamine of rat brain, as measured from the conversion of (14)C-tryptophan into (14)C-5-hydroxytryptamine. The 2-bromolysergic acid diethylamide given in doses fivefold greater than those of lysergic acid diethylamide fails to change the rate of (14)C-tryptophan conversion into (14)C-5-hydroxytryptamine. The effect of D-lysergic acid diethylamide is discussed with regard to its action on brain serotonergic neurons and its psychotomimetic effects.

On the conformations of hallucinogenic molecules and their correlation.

There are only a few possible conformations of D-lysergic acid diethylamide and hallucinogenic derivatives of tryptamine and phenylethylamine. Of these possible conformations there is a high structural correlation among the probable conformations of active hallucinogenic molecules and between these conformations and the known conformations of several central nervous system transmitter molecules.

Lethal mutation rate in Drosophila exposed to LSD-25 by injection and ingestion.

ALTHOUGH attempts have been made to assess the effect of D-lysergic acid diethylamide (LSD-25) on human chromosomes, it has yet to be unequivocally determined when and in what circumstances this chemical is mutagenic. From karyotype analyses of individuals who have ingested LSD-25 some investigators have concluded that it is not mutagenic1,2 while others have reported a high incidence of chromosome aberrations among such individuals3,4 as well as among human leucocytes treated in vivo3. Because of its long standing utility in the detection of induced mutations Drosophila seems to be a likely organism with which to investigate this problem further. Reports have recently appeared which indicate that while LSD-25 is not apparently mutagenic when injected directly in D. melanogaster males in amounts as great as 500 µg/ml. (ref. 5) it is capable of producing X-linked recessive lethal mutations when doses some twenty times larger are used6.

Comparison of effects of LSD and amphetamine on midbrain raphe units.

D-Lysergic acid diethylamide (LSD) given pareriterally produces a reversible cessation of the spontaneous activity of neuronal units in the midbrain raphe nuclei of the rat1. Threshold doses of LSD required to produce this effect are extremely small in relation to those typically used in rats (10–20 µg/kg, intravenously). Substances the behavioural effects of which are similar to those of LSD (for example, N,N-dimethyltryptamine and mescaline) also inhibit raphe units, although none is as potent as LSD2. A variety of other types of drugs (for example, atropine, phencyclidine, chlorpromazine) do not affect the activity of raphe units2. The inhibitory effect of LSD is specific for units in the dorsal and median raphe nuclei; in other mid-brain areas (for example, reticular formation), the drug either has no effect or accelerates unit activity1. According to the fluorescence histochemical method the midbrain raphe nuclei are comprised of serotonin-containing neurones3. Axons of the raphe neurones supply the principal serotonin input to the forebrain4. Large doses of LSD induce a prolonged inhibition of the serotonin-containing neurones1; this inhibition may account for the reduced metabolism of brain serotonin observed after injections of LSD5–8.