Lysergic acid diethylamide: side effects and complications

Psychotomimetic drugs such as lysergic acid diethylamide (LSD) and mescaline have been used increasingly as investigative tools and adjuncts in psychotherapy because they can induce reversible psychotic-like states that allow examination of perception, hallucination and other elements of mental function. Earlier literature and clinical experience suggested both therapeutic potential and the possibility of adverse outcomes including acute panic, prolonged psychotic reactions, depression and, more rarely, suicide, but the incidence and circumstances of such complications were not well characterised. To address this gap, a questionnaire was sent to 62 investigators with experience administering LSD or mescaline in normal subjects or patients, asking for numbers treated, typical dosing, major complications (including suicides, suicide attempts, prolonged psychotic or depressive reactions), screening precautions used, and diagnostic groups excluded. Responses were received from 44 investigators, together reporting data on almost 5,000 individuals and more than 25,000 administrations. The present paper summarises those replies and illustrative case reports to describe the spectrum and frequency of adverse events and to draw implications for safer use in research and therapy.

The investigators conducted a survey of experienced clinicians and researchers by mailing a questionnaire to 62 professionals known to have worked with LSD or mescaline; many respondents had published on these agents. The questionnaire solicited five main items: number of individuals who had received LSD or mescaline, average number of administrations per person, number of major complications (with specific inquiry about suicides, suicide attempts, prolonged psychotic reactions and prolonged depressive reactions), precautions taken prior to administration, and diagnostic groups excluded from treatment. Forty-four responses were returned. From those replies the study team aggregated descriptive information covering nearly 5,000 individuals treated on over 25,000 occasions. Reported LSD dose ranges extended from 25–1,500 (units reported in the source text), and mescaline doses from 200–1,200 (units reported). The survey captured both quantitative counts (overall exposures) and qualitative case descriptions of adverse events. No formal statistical modelling is described in the extracted text; analysis consisted of categorising reported adverse events, noting dose-related patterns, and compiling illustrative case reports and investigator recommendations. The authors also incorporated relevant published reports and clinical anecdotes cited by respondents to provide clinical context and examples.

Overall, the respondents indicated that serious adverse events were relatively infrequent. No consistent pattern of prolonged, serious physical toxicity attributable to LSD or mescaline was identified in the collected reports. Nevertheless, a range of psychiatric and behavioural complications was described across the replies and case vignettes. Immediate adverse reactions: Acute panic, transient paranoid or hyperactive paranoid states, and other episodes of unmanageability were reported. These could include running away from staff, disrobing, accidental self-injury and, less commonly, restrained behaviour. Panic reactions often reflected terror about loss of ego control; they were sometimes precipitated by isolation or anxiety and could be mitigated by conversation, performance tasks or the presence of supportive personnel. Prolongation of the drug state for a day or two was reported in a number of instances; Isbell and others described a few such cases. Somatic complaints and pronounced fatigue were noted in some subjects, sometimes dominating the experience. Seizures and severe physical events: A single convulsion was described (Sandison), and the investigators commented that the incidence of seizures appeared so low that coincidence could not be excluded. No consistent evidence of severe, prolonged physical side effects was found in the survey data. Post-drug mood effects and depressions: Short-lived depressions after the LSD experience were commonly remarked upon. These were attributed variously to post-experience letdown after hyperphoria, to the emergence of shame or guilt that could not be integrated, or to the surfacing of painful autobiographical material. In therapeutic settings, failure to translate insights into changed behaviour sometimes led to inwardly directed aggression and depressive reactions. Suicide and suicide attempts: Completed suicides and attempts were described but appeared to be rare and, importantly, occurred almost exclusively in patients who were already seriously disturbed before LSD administration. The literature cited by respondents reportedly records only one suicide directly attributable in earlier reports, and some described suicides were judged by respondents not to be causally related to LSD (for example, a physician found dead with a NO2 mask on, which the respondent did not attribute to LSD). Several case narratives recounted suicide attempts or completions following administration, typically in subjects with pre-existing severe psychopathology, prior suicide attempts, or poor response to psychotherapy. Prolonged psychotic reactions: A number of prolonged psychotic breakdowns were reported, especially in patients with pre-existing schizophrenia or latent psychotic vulnerability. Dosages in the 100–200 range (units as reported) were associated with some of these longer-lasting reactions, with variable recovery; some required hospitalization and antipsychotic treatment, and a few showed incomplete recovery. Examples included patients developing intensified schizophrenic symptoms, persistent depersonalisation or derealisation, and long-standing disturbances following illicit or repeated use. Dose and setting patterns: Adverse responses tended to be more likely at higher reported doses (noted as above 75 mcg for LSD or above 400 for mescaline in the extracted text), although serious reactions were not strictly dose-dependent. Frequent themes were the importance of supervision, the therapeutic setting and staff demeanour: several cases illustrated that inadequate observation after the acute session or exposure to suggestive or unsupportive personnel could exacerbate risk. Respondents described precautions they used, including pre-administration physical and psychiatric screening, exclusion of subjects with a family or personal history of nervous breakdown or frank psychosis, avoidance of epileptics and the mentally retarded, and hospital-based administration with attendant support. Management measures: Chlorpromazine was recommended as the most satisfactory agent to terminate acute LSD reactions (parenteral 25–50 mg for rapid effect; 50 mg orally for slower onset). Intravenous or intramuscular sodium amytal (0.375–0.75 g as reported) was also cited as effective. Some centres allowed outpatients to go home after the effects subsided under specified conditions (an escort and telephone access), while others required overnight observation. A small number of terminal cancer patients given LSD in one series reportedly experienced no untoward effects.

Huxlr_Y and colleagues interpret the survey results as indicating that, although a broad range of psychiatric complications can occur with LSD and mescaline, most serious adverse outcomes are uncommon when these agents are administered under controlled conditions to selected healthy volunteers. They emphasise that harms—particularly prolonged psychoses and suicidal acts—were mainly observed in patients who were already markedly disturbed prior to treatment, rather than in normal subjects. The authors place their findings in the context of earlier reports, noting concordance with prior concerns about panic, transient psychosis-like phenomena and occasional prolonged reactions, while stressing that systematic precautions appear to reduce risk. Key limitations acknowledged in the text include the incompleteness and possible non-representativeness of the survey (44 of 62 replies; reliance on clinician reports and case vignettes), and the absence of formal statistical incidence estimates in the extracted material. On the basis of the survey and case material, the study team advances practical recommendations for minimising risk: careful subject selection (excluding those with family or personal histories of severe psychiatric illness, epilepsy, or significant organic disease), thorough pre-administration screening, continuous supervision during the acute phase and sometimes beyond, trained personnel familiar with the drug state, readily available measures to counteract or terminate the drug effect (notably chlorpromazine and, where used, sodium amytal), and accessible post-session follow-up. They suggest hospitalisation for higher-dose sessions or for patients at greater risk, and caution in outpatient protocols (overnight observation or an escort and telephone access are advised). The authors conclude that many of the complications described might have been preventable with these safeguards and that, when properly controlled, LSD and mescaline can be administered relatively safely in selected research settings.

From their review of published reports and the survey of 44 physicians, the authors conclude that hallucinogenic drugs such as LSD and mescaline can be given safely to selected healthy individuals provided appropriate precautions are taken. Use in patients carries a higher risk of complications—particularly among those with pre-existing severe psychopathology—but the application of careful screening, constant supervision, trained personnel, and ready antidotal measures can reduce many adverse outcomes. The investigators therefore recommend stringent selection and monitoring procedures to minimise harms in both experimental and therapeutic contexts.