I deeply appreciate the honour that the Royal Medico-Psychological Association has paid me in electing me President for this Year.

Theoretical models ranging from neurological to analytical have been introduced in the hope of providing new insights into psychopathology. The flesh and blood model is of more recent origin in this field. The experimental or model psychosis results from giving “normals” drugs which bring about a psychotic-like experience for a few hours. As is the case with theoretical models, the flesh and blood models are not accurate representations of the naturally occurring psychosis. In fact, the variability manifest in most naturally occurring psychoses makes the existence of an accurate model impossible. A model, whether carefully planned and developed or accidentally discovered, is useful to the extent that it assists us in better understanding the naturally occurring process it approximates. It is useful if it enables us to set up and test hypotheses which contribute additional knowledge about disease aetiology, mechanisms, or treatment. The model psychosis to be studied in this paper is that produced by lysergic acid diethylamide (LSD).

It has often been said that America and Britain are separated by a common language and a similar statement might, with equal justification, be made with respect to some of the misunderstandings between psychiatrists and psychologists. Particularly in the personality field, it is quite obvious that many of the terms used are similar, that some at least of the aims of the two groups are identical, and that methods are freely exchanged. Yet, on the whole, it cannot be said that satisfactory integration has been achieved between these two disciplines.

The study on which we are going to report has its origin in a clinical observation made twenty-six years ago (Schilderand Stengel,1928).

Delirium tremens and toxi-infective delirium are not now common diseases, but are still encountered often enough for their treatment to present problems. Delirium tremens is a medical emergency and intercurrent pneumonia is a serious complication, more likely to occur if the patient's over-activity persists. Toxi-infective delirium is less frequently accompanied by crude over-activity, but this may be a source of significant added strain in the severely ill patient, in whom it is more likely to occur. The standard treatment for delirium tremens is by sedation, and the giving of fluids and glucose. Paraldehyde seems to be the drug of choice. Opinion is divided on whether it is advisable to continue to give moderate amounts of alcohol. Sedation is the standard treatment in toxi-infective delirium, and here barbiturates tend to be used.

Shortly before the end of the last century, Eijkman observed that fowl receiving a diet of polished rice developed a disease which he believed to be of the same nature as human beri-beri. It was subsequently shown that this condition in fowl (polyneuritis gallinarum), and beri-beri in man, could both be cured by the addition to the diet of rice polishings or an extract prepared from them. In 1911, Funk obtained from rice polishings a crystalline substance capable of preventing or curing beri-beri, which he named “vitamine” in view of its evident importance to life, and in the erroneous belief that it had the chemical structure of an amine. Four years later, McCollum and Davis demonstrated that at least two such dietary factors were necessary for growth in rats—“fat-soluble A” and “water-soluble B”. Before long it was recognized that the latter factor had the properties of the antineuritic “vitamine“, and a number of similar organic compounds were discovered, which were essential constituents of the diet in minute quantities, and for which the general term “vitamin”, was agreed upon. For several years it was assumed that water-soluble vitamin B (contained in yeast, rice polish, liver, etc.) was a single entity, but in 1919 Mitchell noted that certain vegetables rich in the antineuritic principle had little power to promote growth, and in 1926 two fractions were distinguished, each essential for growth—thermolabile vitamin B1, containing the antineuritic principle (thiamin), and thermostable vitamin B2.

Cerebral electrostimulation of subconvulsive intensity causes a pronounced increase in the concentration of adrenaline-like substances in the blood (Weil-Malherbe and Bone, 1952b). This effect is presumed to be due to a central action of the current, since these investigators were unable to demonstrate any rise when both electrodes were placed on the same side of the head. The current which was used in these experiments consisted of brief rectangular impulses with a repetition rate of 100 pulses per second (Montagu, 1953). Recently, while experimenting with shorter pulses at correspondingly higher repetition rates, the author observed that the motor response diminished as the frequency was raised, the peak and average current levels remaining constant. This effect, which appeared to be due to the progressive abbreviation of the pulses to the point at which they ceased to be effective motor stimuli, suggested that these conditions might be advantageous in electrostimulation therapy, provided that the autonomic effects were not equally impaired. Firstly, however, it was necessary to determine whether the diminution in the motor effects at the higher frequencies was part of a generalized reduction in the efficiency of cerebral stimulation or whether there was a differential response. Accordingly, with the assistance of Dr. Weil-Malherbe, the blood adrenaline level has been studied in relation to the different conditions of stimulation. The results of this investigation are contained in the present report.

It is evident from many reports published in the last four years that psychological changes can occur during the treatment of physical illness by Cortisone and corticotrophin (A.C.T.H.). There is no doubt, too, that similar mental symptoms have been occasioned by giving either of these agents in therapeutic doses. It is perhaps for this reason that most writers have not distinguished between them in this respect. Thus, the mild mood changes that often occur, and the relatively rare psychotic reactions are usually spoken of as complications of A.C.T.H. or Cortisone therapy. This implies that, in the individual case, these substances would be equivalent in their influence on the mental state; yet there are grounds for suspecting otherwise. The aetiology of these psychological reactions remains obscure, so that any evidence which serves to differentiate the psychiatric side-effects of the two drugs would be of interest.

A number of drugs have been employed in an attempt to increase the mental capacity of oligophrenics. The effect of thiamine on learning demonstrated by Harrell (1943, 1946) led Rudolf (1949, 1950) to use this vitamin in the treatment of oligophrenia. Similarly, the early studies of Zimmermann and Ross (1944) on glutamic acid resulted in a large number of papers on its debatable effect in feeblemindedness (Zimmermann, Burgomeister and Putnam, 1946, 1947, 1948; McCulloch, 1950; Ellson, Fuller and Urmston, 1950; Quinn and Durling, 1950; Lafon, Faure and Bascou, 1952; Oldfelt, 1952). The results of celastrus paniculata on mental defectives have been described by us elsewhere (Morris, MacGillivray and Mathieson, 1953, 1954).

Synaesthesia is defined by Vernon (1937) as a phenomenon in which “a stimulus presented in one mode seems to call up imagery of another mode as readily as that of its own”. The discovery of synaesthesia has sometimes been wrongly attributed to Galton. Galton (1883) certainly describes instances, but reports on earlier descriptions, for example those published in 1881 by Bleuler and Lehmann.

Because of their rapidity of onset, brevity of action and relative safety, the choline succinic ester derivatives, in the last two years, have almost completely superseded tubocurarine, gallamine and decamethonium as muscle relaxants in electroplexy. The literature now contains a number of reports of prolonged respiratory arrest associated with the use of these new relaxants. In publishing the results of early experience at Long Grove with three of the new compounds, Monro et al. (1953), tended to favour Scoline with thiopentone in a body-weight dosage using a one-syringe technique. The infrequent occurrence of excessive apnoea proved to be no great problem and was easily dealt with. However, during subsequent work in the same hospital, we were impressed by the markedly more abrupt action of suxethonium (Brevidil “E”) and felt that further investigations into its clinical properties might yield some reward.

The use of chemically induced convulsive therapy introduced by Von Meduna in 1934 was followed by the introduction of electric convulsive therapy by Cerletti and Bini in 1937. The latter method is now of almost universal use. The main reasons for the change over were the elimination of the unpleasant aura experienced in connection with the leptazol fit and the fact that body accidents were said to be less frequent with E.C.T. There does not appear to be any evidence of greater therapeutic efficiency with E.C.T. Bini and Bazzi (1949) in summarizing statistics covering twelve thousand cases, found no difference in the remission rates in the two therapies. Dedichen (1946) indicated that the value of the two therapies in depressions was similar and Ross (1946) found this also for cases of acute excitements.

It is generally assumed that an activation of the sympathetic system plays an important part in the therapeutic efficacy of convulsive treatments, be it as an unspecific result of stress or owing to a more circumscribed stimulation of specific centres in the hypothalamus and elsewhere. Such an effect has been postulated on the basis of various changes observed after convulsions, such as a rise in blood pressure (Accornero, 1940; Bini and Puddu, 1940; Piette, 1950), hyperglycaemia (Castelluci, 1940; Kessler and Gellhorn, 1941), leucocytosis and lymphocytosis (Gellhorn and Frank, 1948, 1949; Michael, 1949) and eosinopenia (Altschule, Parkhurst and Tillotson, 1949). Pupillary dilatation and contraction of the nictitating membrane have been described in cats (Gellhorn and Darrow, 1939). More direct evidence is provided by the finding that the adrenaline stores of the adrenal medulla are decreased after electrically produced convulsions (Pekkarinen, Hakala and Hyppönen, 1952).

The chemical compound 3-ortho-toloxy-1,2-propanediol, known as mephenesin, Myanesin or Tolserol, was shown by Berger and Bradley in 1946 to depress reflex excitability of the spinal cord and to have a depressant action at higher levels of the central nervous system in higher dosage. Other investigators confirmed this and the drug has been found effective for the spasticity and tremor of some neurological conditions.

In 1946 Berger and Bradley showed that mephenesin caused muscular relaxation and, in the same year, Stephen and Chandy (1947) reported that the intravenous administration of mephenesin to human subjects was usually accompanied by a feeling of euphoria and relaxation. The clinical trial of mephenesin in neurotic states associated with tension and anxiety was a natural corollary of these findings. Reports of its efficacy have been conflicting, but this is hardly surprising when a new drug is introduced for the treatment of a common disorder whose natural course may be either chronic or self-limiting, which is subject in a marked degree to apparently spontaneous fluctuations in intensity and on which the effects of suggestion are notorious. The assessment of therapy is made more difficult by the fact that there is no satisfactory objective method of measuring changes in the degree of anxiety; the investigator must either use tests the relevance of which many people will dispute or he must rely on clinical assessment, a subjective judgment very dependent on the skill and experience of the clinician. As Bradford Hill (1951) has stressed, clinical assessment can only be given full weight in a therapeutic trial when the possibility of enthusiasm or scepticism on the part of the clinician is eliminated. Such elimination of bias is best achieved by treating one group of patients with the drug and another group with a placebo, the clinician, nursing staff and patients not knowing to which group any particular patient has been assigned.

Largactil is one of the phenothiazine group of compounds. It is, therefore, related to promethazine (phenergan) and diethazine (diparcol). It is also known as R.P. 4560 and chlorpromazine. It has been used on the Continent in psychiatric cases since 1951, because of the relaxation and calm it produces. It has been on trial at Netherne Hospital since 1953 and 80 patients have received this treatment.