Mental changes experimentally produced by d-lysergic acid diethylamide tartrate

The paper opens with a historical overview of early observations of the effects of d-lysergic acid diethylamide (LSD), beginning with Albert Hofmann's self-observations and subsequent investigations by several clinicians. Earlier experimental work by W. A. Stoll, Condrau, Becker and others is summarised as reporting disturbances in perception (notably visual hallucinations), vegetative and motor symptoms, changes in affect and thought processes, variable disturbance of consciousness but preserved judgement, and a striking potency of very small oral doses. Some investigators emphasised similarities to psychotic syndromes or diencephalic dysfunction, while others highlighted the drug's “psychoticum” qualities and its variable expression across individuals. Miss and colleagues set out to add to this literature by conducting controlled experimental administrations of LSD to healthy adult volunteers, systematically observing the psychiatric picture, autonomic and some neurophysiological measures, and selected psychological tests. The study aimed to characterise the mental changes produced by small oral doses of LSD, describe the time course of the reaction, and explore electrophysiological and psychological correlates that might clarify how the drug affects higher nervous-system function.

LSD was administered 17 times to 15 healthy adult volunteers (10 men, five women), who were students, nurses and physicians aged 19–48 years; two female volunteers underwent two experiments each. The preparation, supplied by Sandoz, was an aqueous solution containing 20 gamma per cc (1 gamma = 0.000001 g = 1 microgram). Doses ranged from 20 to 90 gamma, with most administrations approximating 1 gamma per kilogram of body weight. The drug was taken orally in about half a glass of water at 8:30 a.m. after an overnight fast; a light breakfast was provided about 30 minutes later. Subjects were under continuous surveillance by at least one of the experimenters for the first five hours in a relatively soundproof room, with occasional tape-recording of verbal material. Observations continued intermittently during the afternoon and the following morning. Routine neurological and circulatory examinations were not performed, although signs in these domains were noted opportunistically. In three subjects the investigators administered autonomic drugs (adrenaline or atropine) before and after LSD to probe autonomic lability. Electroencephalograms (EEGs) were recorded in nine experiments at or near two hours post-administration and compared with baseline recordings. Rorschach tests were administered to five subjects (four with baseline controls) and Concrete–Abstract Thinking tests (proverbs) to two subjects during the reaction. The study was observational and descriptive; no specific inferential statistical analysis or formal blinding is reported in the extracted text.

Subjective symptoms occurred in all experiments, typically beginning 15–90 minutes after ingestion and persisting sporadically through the day. The most frequent complaints were decreased appetite, headiness, giddiness, faintness, tremulousness, a subjective sense of poor coordination, weakness, chilliness, abdominal sensations, numbness, headache, lightness and nausea. Autonomic phenomena such as flushing, sweating, shivering, tachypnoea, salivation and urinary urgency were commonly recorded. Disturbances in thinking and speech were universal. The predominant findings were difficulty with expression and concentration, retardation of thought more often than acceleration, blocking, and impaired abstract thinking; less common were poverty of thought, looseness, distractibility, flight of ideas and intermittent automatic or cathartic speech. These cognitive disturbances typically emerged within 45 minutes and could last into the late afternoon. Alterations in mood and affect were present in all experiments; clear affective blunting and suspiciousness were most frequent. Tension, feelings of unreality and body-image disturbance were common. Both euphoria (shallow elation) and depressive, dependent or passive states occurred, with indifference and blunting tending to be more prolonged while suspiciousness and hostility were more transient. Perceptual disturbances were common and dominated by visual phenomena: rippling or movement of objects, changes in size and shape, and colour misperceptions. Less frequent were gustatory and auditory disturbances. Time sense was disrupted in 11 of 17 experiments, with experiences of acceleration, retardation or non‑existence of time. Morbid ideas such as ideas of reference and influence were observed; formed visual hallucinations were reported, with isolated auditory, gustatory and haptic hallucinations. Objective behavioural changes were seen in 15 experiments, usually underactivity with reduced initiative and spontaneity; psychomotor signs included involuntary smiling, giggling and laughing. Neurological signs were sparse: transient dysarthria occurred in five experiments and no consistent deficits in gait, reflexes or muscle strength were observed. In two subjects modest transient rises in blood pressure (systolic +10–20 mmHg, diastolic +10 mmHg) were recorded about 1.5 hours post-dose. The course of the response was described in three broad phases over 12–16 hours, with an occasional fourth phase of after-effects lasting one to several days. Phase I (prodrome) began 20–90 minutes after dosing; Phase II (height of reaction) ranged roughly from one to over five hours post-dose and showed the most pronounced psychopathology; Phase III extended from the end of Phase II to evening and was characterised by reduced activity, poverty of thought and blunted affect resembling a simple schizophrenic reaction. Phase IV, variably present, consisted of subdued or introspective changes for days in a few subjects. The authors emphasised that symptoms tended to occur in waves and that Phase III was often more uniformly schizoid than the more heterogeneous Phase II. EEG recordings in nine experiments showed modest changes: increased muscle artefact associated with restlessness in most recordings, a characteristic increase in alpha rhythm rate by about 1–3 cycles per second in most subjects (one showed slowing), and diminished responsiveness to hyperventilation; overall EEG changes were judged slight relative to the clinical picture. Rorschach protocols during the reaction were abnormal in all five tested subjects: three yielded schizophrenic-type profiles (one strongly schizophrenic with autistic thinking and poor organisation), one was paranoid, and one borderline. In the two Concrete–Abstract tests, concrete responses predominated and abstraction required effort; responses often showed overgeneralisation and tangentiality resembling schizophrenic thought. Selected case vignettes illustrate typical patterns: Case 1 (20 gamma) showed early headiness, intermittent blocking, transient suspiciousness and visual distortions, followed by a withdrawn, indifferent Phase III; Case 6 (60 gamma) demonstrated severe impairment of symbolic expression (near-catatonic mutism) with later visual hallucinations at home in the evening; Case 11 (70 gamma) had marked detachment, body‑image disturbance, ‘paralysis of will’, transient autonomic signs and later recovery by next day. Memory for the experiences was generally intact and subjects retained capacity for self-appraisal; anxiety was infrequent and usually limited to the prodrome. All subjects indicated willingness to repeat the experiment. In summary, the principal findings were robust, reproducible alterations across cognition, affect, perception and autonomic function after small oral doses of LSD, with many features resembling schizophrenic turmoil or simple schizophrenic states.

The investigators interpret their observations as showing that minute oral doses of LSD produce definite and sometimes striking mental changes that, in many respects, simulate schizophrenic and affective psychoses. They emphasise the prominence of disturbances in thinking and speech, affective blunting and detachment, perceptual alterations (especially visual) and autonomic instability. The authors note that Phase II often resembled a schizophrenic turmoil state while Phase III tended toward a simple schizophrenic reaction; transient paranoid trends and isolated manic‑like features were also observed. In comparing their results with earlier research, the writers find general agreement with reports by Hofmann, Stoll, Condrau and others regarding perceptual changes, psychotic‑like syndromes and the remarkable potency of small doses. Rorschach and proverb tests in their series similarly pointed to schizophrenic‑like disruptions of organisation and abstraction. One subject's dramatic cathartic episode at the largest dose raises the possibility that higher doses can elicit psychological release in some individuals, though this was uncommon in the sample. Physiological interpretation is cautious: the authors consider involvement of higher cerebral centres, with some evidence pointing to diencephalic effects (vegetative signs, involuntary laughing) and other findings suggestive of cortical involvement (impaired symbolic expression and modest EEG changes). They speculate, tentatively, about a selective inhibitory action on sympathetic pathways or intracortical sympathetic circuits, producing sequential effects at different levels of the nervous system; this is presented as conjecture rather than established mechanism. Animal findings cited in the text (excitement in anaesthetised rabbits, catatonia-like muscle tone in dogs and cats at high doses) are invoked to argue that LSD acts on central nervous structures. The study acknowledges limitations implicit in the extracted text: routine neurological and circulatory examinations were not undertaken, some phases (notably the after-effect Phase IV) were not closely observed in all subjects, and the extent to which baseline personality contributed to individual variability remains undetermined. The authors conclude that further study is indicated because LSD, at very small oral doses, reliably produces a range of phenomena that closely mimic certain features of schizophrenic and affective psychoses, and because these effects may offer avenues for understanding psychotic symptoms and central nervous system action—observations they argue merit additional investigation.