Research ethics aspects of experimentation with LSD on human subjects : a historical and ethical review, Bodnár Kristóf János & Kakuk Péter, 2018

Research ethics aspects of experimentation with LSD on human subjects : a historical and ethical review

Bodnár Kristóf János, Kakuk Péter

Medicine, Health Care and Philosophy
© Springer Nature B.V. 2018


In this paper our aim is to examine whether research conducted on human participants with LSD-25 (lysergic acid diethylamide) raises unique research ethical questions or demands particular concerns with regard to the design, conduct and follow-up of these studies, and should this be the case, explore and describe those issues. Our analysis is based on reviewing publications up to date which examine the clinical, research and other uses of LSD and those addressing ethical and methodological concerns of these applications, just as some historical examinations of this subject. The first chapters of the paper give an overview regarding the history of LSD-research with human participants, healthy volunteers and patients alike. The remaining chapters have a focus on questions regarding the potential ethical issues of such human trials in the contemporary research ethics framework. We also consider briefly political and regulatory issues regarding this substance that possibly affect its clinical and research applications.

Keywords : Research ethics · Clinical trial · Lysergic acid diethylamide · LSD research · Psychedelic research



“If people did not sometimes do silly things, nothing intelligent would ever get done.”
Ludwig Wittgenstein.

From popular magazines’ leading articles to in-depth reviews in renowned medical journals, a growing number of reports could be found on the (re)emerging interest in researching the so-called “psychedelic drugs”—a group of substances that include lysergic acid diethylamide (from now on: LSD) as well. New studies are investigating LSD’s applicability and effects on different conditions and with various populations. For example, in 2016 alone more than 10 experiments were reported that involved LSD administered to human subjects. At the same time, however, there has been little reflection on the research ethics issues involved in this subject. One of the few papers to discuss such issues noted that, “to date, the ethical factors involved in research using controlled drugs have not been well described, recommendations have not been well developed, and there is almost no evidence-based guidance on how to assess these factors and proceed” (Andreae et al. 2016, p. 42).

In this paper we examine whether research conducted on human participants with LSD raises unique research ethics questions. In what sense do these studies demand particular attention with regard to the design, conduct and follow-up of these studies and what kind of special research ethics issues must be considered? Beginning with an overview of the exciting history of such research, we will provide a general assessment of research with LSD with human participants. In this second part we are following the ethics framework provided by Emanuel et al. which was developed for the assessment of major research ethics questions raised by clinical trials.ű.

The history of LSD research

The studies with LSD on human participants from the beginning of the 1950s include randomized and other controlled trials, experimental therapeutic uses, or close empirical observations without a control group, and informal experiments—a part of these being conducted on healthy volunteers, another part on patient populations. The number of such trials up to this date is estimated to be around 200, with several thousand publications explaining or describing those, not involving the numerous uncontrolled, but experimental applications, with tens of thousands of participants (Das et al. 2016; Passie et al. 2008; Sessa 2018).

The first documented—famously non-voluntary—experiment with LSD was conducted by Albert Hofmann on himself after he unintentionally synthesized it for the first time in 1938; this followed numerous animal experiments (Hofmann 1979). Scientific discussion on LSD first were published in scientific papers in 1943, and Joel Elkes conducted the first psychiatric experiment with LSD in 1951 (Dyck 2015B). The next decade witnessed widespread and diverse research interest in investigating this compound. Between 1951 and 1966 roughly 1000 clinical publications described the experimental uses of LSD, most of them concerned psychedelic assisted psychotherapy, with approximately 40,000 patients involved (Grinspoon and Bakalar 1981). These studies included about 120 LSD trials that were conducted with more than 1700 subjects and sponsored by the Federal government in this period with $4,000,000 of Federal financial support (Pollan 2015).

These experiments and therapeutic research were diverse in terms of their areas of interest and methodology: some researchers, like Joel Elkes, following Hofmann’s trail, began by conducting self-experimentation (Dyck 2015B; Novak 1998). Besides the basic researches addressing the fundamental questions of safety, toxicity, pharmacological and pharmacokinetics issues, professionals conducted
a large number of applied, therapeutic studies with LSD. Abramson put forward his model psychosis theory that regarded LSD-states as models of chemically induced psychosis (LSD labelled and explained as “schizotoxic” compound) that might be revealing in understanding mental disorders through such biochemical means. Other studies were performed to test recall and abstraction and to produce improved insight. Experimentation on patients with mental disorders included studies investigating the psychologically therapeutic potential of the substance that might even contribute to considerable emotional ventilation in schizophrenics (Das et al. 2016, p. 216–217). In this respect, the most
widespread application of LSD was—and remains to be—its usage as an adjunct psychotherapy, i.e. as an adjuvant substance to assist psychotherapy of various sorts. Two dominant forms were most frequent (actually, so widespread that Stanislav Grof alone between 1956 and 1968 was present at
1.100 LSD and psilocybin sessions (Oram 2014)) :

“One emphasized the mystical or conversion experience and its after effects; the other concentrated on exploring the labyrinth of the unconscious in the manner of psychoanalysis. Psychedelic therapy, as the first of these was called, involved the use of a large dose of LSD (200 μg or more) in a single session and was thought to be helpful in reforming alcoholics and criminals, as well as in improving the lives of normal people. The second type, psycholytic (literally, mind-loosening) therapy, required relatively small doses (usually not more than 150 μg) and several or even many sessions; it was used mainly for neurotic and psychosomatic disorders. (Grinspoon and Bakalar 1981, p. 275).

These LSD assisted psychedelic and psycholytic psychotherapies addressed several psychological problems, ranging from—as it was called then—“obsessional neurosis” through major depression, generalized anxiety and even psychotic conditions. One particularly promising field within this area of therapeutic application was the adjuvant use of LSD combined with counseling to reduce anxiety, depression, and pain in patients with advanced cancer. These studies involved more than one hundred patients, and this use of LSD was shown to be safe in this population (cf. Das et al. 2016; for a general outline and overviews—contemporary and recent alike—of these psychedelic and psycholytic LSD assisted therapies, see also Dyck 2015a; Passie 1997).

Humphrey Osmond coined the term “psychedelic” to denote and emphasize the mind-expanding, mystical experience- evoking capability of LSD and other, related psychotropic substances. He and his team used LSD assisted psychotherapy in treating chronic alcoholics, which was one of the most researched areas of LSD usage for therapeutic purposes together with the above mentioned application in anxiety of terminal patients. More recent reviews suggest that this could be regarded as a general success, both in terms of efficacy and having a very good side-effect profile at the same time (Das et al. 2016; Dos Santor et al. 2016; Krebs et al. 2012). A surprising fact—mostly from the perspective of a research ethics focused article—is that even Henry Beecher was involved as a principal investigator in one of these early experiments on healthy volunteers (von Felsinger et al. 1956).

Sydney Cohen, a leading figure in LSD (and psychedelic) research at that time has drawn the following conclusion regarding the overall—somatic and psychological—safety of LSD’s controlled usage: he computed that the number of suicides was 0.4/1000, thus concluded that complications were‚ “surprisingly infrequent”, and that, when given in a medical setting, “LSD and mescaline were safe” (Novak 1998, p. 23). These claims, based on the exploration of the first decades of LSD research on the relative safety of LSD itself and its application as an adjuvant substance are backed by Das et al.’s thorough and up-to-date review, as it summarizes safety issues: “Classic hallucinogens have very low physiological toxicities, with no evidence of resulting organ damage or neuropsychological deficits even at very high doses. (…) For the large majority of participants, the most relevant safety concern is the potential for dangerous and erratic behavior resulting from the intense subjective experiences with these drugs.” However, underlining, at the same time that “(…) the absolute contraindications of LSD
use are physical conditions precluding marked excitement (e.g. cardiovascular disease), pregnancy, epilepsy, paranoid personality, overt psychosis, organic-toxic cerebral disorder, and so on.” (Das et al. 2016, pp. 221–222).