Carl C. Pfeiffer

The effect of the hallucinogenic drugs LSD-25 and mescaline on the electroretinogram.

There is a controversy in the literature concerning the precise manner in which d-lysergic acid-dl-hydroxybutylamide-2 (LSD-25) and mescaline induce visual hallucinations in normal human subjects. I t is essential that this problem be clarified since the designation of these 2 drugs as “psychotomimetic” is influenced by the concept that the central nervous system participates in the production of these hallucinations. Our present knowledge of this problem has arisen from clinical and experimental studies on humans and on cats. Kluver5 has described in great detail the visual hallucinations induced in human subjects. These hallucinations take 2 forms: early appearing geometric patterns in many colors, and later appearing panoramas. A publication by StolP depicts hallucinations produced by LSD-25 with line drawings of honeycombs, lattices, filigrees, and ruffles. These patterns appear to the subject in luminescent yellow, green, and red colors. These colors are similar to the bright phosphores that appear in the visual field after the mechanical stimulation of the eyeball. These hallucinations do not appear to subjects unless their optic nerves are intact.’, Physiologists have studied the effect of LSD-25, in both nontoxic and toxic doses, on the visual pathways of cats. Purpura6* has deduced that this drug facilitates synaptic transmission in the central nervous system, and Rovetta* finds spikes on the occipital cortex that are similar to the spikes caused by strychnine. A perusal of these clinical and experimental data indicates that the source of the visual hallucinations might be in the retina itself rather than in the central nervous system. The present study investigates the extent to which the retina is involved in the production of visual hallucinations induced by LSD-25. The study is based on the principle that an electrical potential accompanies activity in any nervous element. Action potentials may be detected anywhere on the surface of the eyeball following marked changes in the illumination of the retina: These potentials indicate activity in the retina, and they occur only when retinal elements are transmitting electrical impulses. It follows, therefore, that such an electroretinogram would be induced by the hallucinogens when the illumination of the eye remained constant only if the retina were participating in the production of spontaneous visual experiences. I t seemed worthwhile, therefore, to investigate the effects of hallucinogenic drugs on the retinas of cats.

Effects in normal man of α‐methyltryptamine and α‐ethyltryptamine

DL‐α‐Methyltryptamine methyl sulfate in oral doses of 20 mg. and DL‐α‐ethyltryptamine acetate in oral doses of 150 mg. were compared objectively and subjectively in a group of trained, normal human volunteers. Blood pressure, pulse rate, pupil diameter, oral temperature, and grip strength were recorded hourly. Subjective effects were recorded 3 and 24 hours after administration of the drugs.

Parasympathetlc Neurohumors; Posslble Precursors and Effect on Behavior1

Publisher Summary Schizophrenias occurs as a group of diseases of varying biochemical etiologies and, therefore, any correlation of improvement or deepening of the schizophrenic state should be vigorously explored to ascertain the possibility that biochemical subclasses of the schizophrenias may be definitely established. The diagnosis is based on the patients history, chronicity of the disorder, behavior, motor patterns, and verbal exhaust. Various model hypotheses are explored, elaborated, and used without attempt to document these hypotheses in all instances by laboratory data in the experimental animal. Various unknown parasympathetic neurohumors may be more important in human physiology than the two esters that are thought to occur in mammalian tissue, namely acetyl and propionylcholine. Structure-activity-relationships (SAR) analysis indicates that an asymmetric α-carbon atom may occur in the acid fragment and that a β-substituent (possibly hydroxy) on a choline-like compound might be present to provide an asymmetric α-carbon. The neurotransmitters may of course be represented by a family of compounds rather than by a single compound. The compound should have greater muscarinic effect than acetylcholine that should occur with a β-carbon substitution.

Comparative study of the effect of meprobamate on the conditioned response on strychnine and pentylenetetrazol thresholds, on the normal electroencephalogram, and on polysynaptic reflexes.

Meprobamate has been introduced as a safe prescription drug on the basis of the work of Berger et ~ l . l ~ According to the published data of this group, meprobamate has a striking tranquilizing effect on monkeys, antidotes strychnine, abolishes flexor reflexes, and elevates the pentylenetetrazol threshold. It is also claimed that the drug does not affect the normal electroencephalogram (EEG), or produce sleep waves or barbiturate spindles in the EEG, but that it does produce a synchronization of thalamic recordings from depth electrodes in the cat, where recordings show slowing with greater regularity and higher voltage. Thus, entirely on the findings of a single pharmacological laboratory (as far as we have been able to ascertain from a careful perusal of scientific literature), this drug has been launched into therapeutics as a tranquilizer with muscle relaxant action, that is, a long-acting mephenesin. I t therefore behooves other pharmacological investigators to confirm or disprove these claims and to compare the drug to other known internuncial neuronal depressants and central-nervous-system (CNS) drugs. Such a comparison is attempted in this paper.

THE PREDICTABLE VALUE OF ANTICONVULSANT INDICES

Anticonvulsant testing, when accurately performed, should not be viewed by industry as a procedure that is limited to the possible discovery of better anticonvulsants, but rather as the delineation of drug effects on the central nervous system (CNS), which may result in new compounds with broad usefulness in epilepsy, neuroses, depressions, psychoses, parkinsonian tremors, and mental retardation. While the need is great for better anticonvulsants, the commercial application of a new product in this limited field will hardly encourage a research director to provide adequate funds and personnel for the requisite testing program. A broader vista is thus necessary, and this is exemplified by the fact that reserpine will lower the electroshock threshold of animals’ and meprobamate will significantly raise the threshold of, and lower the mortality from, intravenous strychnine infusions.2 The modicum of commercial success of these 2 drugs should turn the mind of the treasurer toward an anticonvulsant testing program in spite of possible deficiencies in his previous biological training. The need exists, however, for more effective and safer anticonvulsant drugs, since the presently available anti-petd mal drugs possess toxic hazards. Some anti-grand ma1 drugs such as mesantoin and phenacemide are toxic, and safe drugs for the treatment of diphenylhydantoin-resistant psychomotor seizures are nonexistent. At present, theories are unavailable to explain the serious side effects such as skin rashes, bone marrow depression and liver impairment that have plagued the therapy of epilepsy when new anticonvulsants are used. Perhaps the most important factor in these unexplained drug reactions is the fact that antiepilepsy drugs are usually given (daily and continuously) to patients in increasing dosage until the seizures are controlled or the patient manifests signs of intoxication. The introduction of plasma-level determinations of anticonvulsant drugs may introduce a greater margin of safety in that the vagaries of individual intoxication by the drug may then be regulated by lowering the individual’s daily dose.

Experimental seizures in man and animals with acute pyridoxine deficiency produced by hydrazides.

Abstract Three hydrazides, semicarbazide, thiosemicarbazide and thiocarbohydrazide, were given orally to schizophrenic patients to produce a temporary epileptic state for a 1 to 5 hour period. During this time, seizures may occur spontaneously or they may be induced by auditory or photic stimulation. The photic stimulation induced seizure or spontaneous seizure is thought to be less traumatic than electrically induced seizures. Pyrodoxine will antidote completely this temporary epileptic state. Thiocarbohydrazide is the most potent hydrazide for the production of this epileptic state. An oral dose of 100 to 200 mg. of Thio-C will produce a spontaneous seizure in 1 to 3 hours. Hydrazides produce vomiting as a side action which is apparently central in origin. Electroencephalographic studies in animals and man indicate that these seizures all probably originate subcortically. It remains to be determined whether hydrazide convulsions are more effective in schizophrenia than are electrically induced convulsions.

The stimulant effect of 2‐dimethylaminoethanol (deanol) in human volunteer subiects

A double blind comparison of deanol, 10 to 30 mg. base, as the tartrate salt was made with an identical placebo in 35 volunteer subjects. No significant changes from the controls were observed in blood pressures, pulse rate, muscle strength, hand tremor, vital capacity, or body weight. Blood cholesterol levels were not changed. Blood protein bound iodine showed a slight tendency to decrease at the start of therapy, but this was not statistically significant. Gastric acid secretion was not changed, although volume of secretion was. Of the psychological and subjective responses, the significant findings were an increase in muscle tone, better mental concentration, and changes in sleep habits which were (1) less sleep needed, (2) sounder sleep, and (3) absence of the customary period of inetficiency in the morning in the deanol‐treated group.

Effects in man of single and combined oral doses of reserpine, iproniazid, and D‐lysergic acid diethylamide

The use of d‐lysergic acid diethylamide, LSD, as a reference standard for the evaluation of psychopathologic symptoms was tested. A group of healthy male volunteers took weekly doses of LSD in order to become familiar with the temporary mental changes induced by the drug.

Report of the subcommittee on position and status of the clinical pharmacologist in drug research

The new F. D. A. regulations direct attention to the clinical pharmacologist and have suddenly created a broad demand for his services. Yet there is no clear‐cut de:6.nition of a clinical pharmacologist or of clinical pharmacology; there are no generally accepted standards for the education and training of clinical pharmacologists and, though a journal with such a title is now in its fourth annual volume, there exists no collected body of literature or any textbook. If only for the legal considerations, an authoritative statement on the meaning and scope of clinical pharmacology is urgently needed. Since an important public function is involved, this subcommittee puts forward the statement which follows in the hope it will lead to the establishment of appropriately high standards for clinical pharmacology and clinical pharmacologists.