ArticlePDF Available

Regulation of human research with LSD in the United States (1949-1987)

Abstract

Human research with hallucinogens such as lysergic acid diethylamide (LSD) has been ongoing in the USA since 1949. During the 1960s, LSD was investigated for a variety of psychiatric indications, including the following: as an aid in treatment of schizophrenia; as a means of creating a “model psychosis”; as a direct antidepressant; and as an adjunct to psychotherapy. Studies with all drugs, including LSD, have always been conducted under federal regulatory controls, including the 1938 Food Drug and Cosmetic Act (FDCA; which ensured the safety of drugs) and the 1962 Kefauver-Harris Amendments to the FDCA (which described appropriate scientific methodology and ensured drug efficacy). This paper details how the 1962 Amendments introduced numerous safety and efficacy requirements that must be in satisfied during clinical drug research—and how human studies conducted with LSD in the 1960s struggled with their fulfillment. Information is provided from Senate hearings, case law, and interviews with key investigators. Examples are also drawn from scientific papers and symposia published during and since that period, with a focus on information from clinical studies conducted with LSD by psychiatrist Albert Kurland at the Spring Grove State Hospital, near Baltimore, MD. While Kurland largely conformed with these new regulations, other investigators often fell short of complying with scientific standards and federal requirements. Thus, the human hallucinogen studies of the 1960s are best understood as providing pilot data on safety and efficacy, as well as testable hypotheses for current hallucinogen studies conducted under modern scientific and regulatory standards.
REVIEW
Regulation of human research with LSD in the United
States (1949-1987)
Katherine R. Bonson
1
Received: 5 July 2017 /Accepted: 26 October 2017 /Published online: 17 November 2017
#This is a U.S. government work and its text is not subject to copyright protection in the United States; however, its text may be subject to foreign
copyright protection 2017
Abstract Human research with hallucinogens such as lysergic
acid diethylamide (LSD) has been ongoing in the USA since
1949. During the 1960s, LSD was investigated for a variety of
psychiatric indications, including the following: as an aid in
treatment of schizophrenia; as a means of creating a Bmodel
psychosis^; as a direct antidepressant; and as an adjunct to psy-
chotherapy. Studies with all drugs, including LSD, have always
been conducted under federal regulatory controls, including the
1938 Food Drug and Cosmetic Act (FDCA; which ensured the
safety of drugs) and the 1962 Kefauver-Harris Amendments to
the FDCA (which described appropriate scientific methodology
and ensured drug efficacy). This paper details how the 1962
Amendments introduced numerous safety and efficacy require-
ments that must be in satisfied during clinical drug research
and how human studies conducted with LSD in the 1960s strug-
gled with their fulfillment. Information is provided from Senate
hearings, case law, and interviews with key investigators.
Examples are also drawn from scientific papers and symposia
published during and since that period, with a focus on informa-
tion from clinical studies conducted with LSD by psychiatrist
Albert Kurland at the Spring Grove State Hospital, near
Baltimore, MD. While Kurland largely conformed with these
new regulations, other investigators often fell short of complying
with scientific standards and federal requirements. Thus, the
human hallucinogen studies of the 1960s are best understood
as providing pilot data on safety and efficacy, as well as testable
hypotheses for current hallucinogen studies conducted under
modern scientific and regulatory standards.
Keywords Hallucinogen .LSD .Clinical .Regulation
Every month, it seems there is another story in the news
heralding a clinical study being conducted in the USA with a
hallucinogenic drug. Some of these studies are engaged in eval-
uating the potential medical applications of hallucinogens, while
others are investigating scientific questions that are pharmacolog-
ical or psychological in nature. But all of these studies have one
thing in common: as modern clinical studies, they are being
conducted under an investigational new drug (IND) application,
an oversight mechanism by the Food and Drug Administration
(FDA) for human research with drugs. These hallucinogen stud-
ies additionally all have approval by an Institutional Review
Board (IRB) to ensure subject safety, all study participants have
signed an informed consent document, and the research is being
conducted under a Schedule I license from the Drug
Enforcement Administration (DEA), among other regulations.
This was not always the case, though.
This paper will discuss how changes in FDA policies in the
1960s that oversee all drug research in the USA introduced nu-
merous safety and efficacy requirements that affected clinical
research with hallucinogens such as lysergic acid diethylamide
(LSD). (LSD is the focus of this paper because there is vastly
more historical information available compared to psilocybin or
mescaline.) This review uniquely and systematically evaluates
these studies in terms of their compliance with the new regula-
tions. These regulations critically improved scientific standards
and subject protections, which led to the curtailment of many
unethical research practices common at that time for clinical
research with any class of drugs. This is an important history
*Katherine R. Bonson
katherine.bonson@fda.hhs.gov
1
Controlled Substance Staff, Center for Drug Evaluation and
Research, Food and Drug Administration, Silver Spring, MD 20910,
USA
Psychopharmacology (2018) 235:591604
https://doi.org/10.1007/s00213-017-4777-4
because FDA has often set the standards for human research and
drug development for the rest of the world. However, for reasons
detailed below, laboratories that wished to continue conducting
human studies with LSD in this era often struggled with the
fulfillment of specific elements in the new regulations. This ulti-
matelyledtoadeclineinLSDresearch.
Although we may wish to excuse the methodological discrep-
ancies in the older hallucinogen studies as being from another
era, we cannot do so and at the same time treat the data from
these studies as valid and reliable for informing modern regula-
tory decision-making. Thus, the early studies with LSD are best
understood as providing valuable pilot data on safety and effica-
cy, as well as testable hypotheses for future studies conducted
under current scientific and regulatory standards.
The early years of LSD treatment and research
The history of research with hallucinogens in the USA is
exemplified by how LSD was investigated in humans in the
years following its famous rediscovery (and colorful bicycle
ride) in 1943 by its inventor, Swiss chemist Albert Hofmann at
Sandoz Pharmaceuticals (Hofmann, 1983). It was only a few
years later, in 1947, that the first scientific study was published
on the effects of LSD in 16 healthy volunteers (to observe
their responses) and in 6 patients with psychosis (to see if it
would alter their symptoms) (Stoll 1947). The principal inves-
tigator, Swiss psychiatrist Werner Stoll, also tested the drug on
himself, so that he might experience a schizophrenic state of
mind. Two years later, in 1949, Boston psychiatrist Max
Rinkel and Los Angeles psychiatrist Nick Bercel personally
brought the first Sandoz LSD to the USA for testing (Lee and
Shlain 1985; Hagenbach and Werthmuller 2011).
Under the 1938 Food Drug and Cosmetic Act (FDCA),
before a drug could be marketed nationally in the USA, drug
companies needed to submit data to FDA under a new drug
application (NDA) demonstrating the safety of their drug. (For
regulatory purposes, a Bnew drug^is one that has not been
approved in the USA, regardless of how old the drug actually
is or whether it has been approved in other countries. It also
includes FDA-approved drugs that are proposed for a new
indication, formulation, dose, or patient population.)
Notably, the FDCA provided for an exemption to the re-
striction on distribution. Drug companies were allowed to dis-
tribute drug samples nationally, prior toNDA approval, if they
were Bintended solely for investigational use by experts qual-
ified by scientific training and experience to investigate the
safety of drugs^(FDCA, Sec. 505 (i), 21 U.S.C. § 355(d)). In
fact, this manner of interstate distributiona company send-
ing drug samples to a doctor, who then tried them on a pa-
tientis how thalidomide came to be tested in pregnant wom-
en in the USA. This resulted in children with phocomelia,
despite the fact that an NDA was never approved for
thalidomide because of the heroic actions of FDA medical
reviewer Frances Kelsey in 1960 (Kelsey 2014).
Many companies utilized this system of distributing inves-
tigational drugs, including Sandoz. This meant that even
though Sandoz never submitted an NDA, samples of LSD
were shipped (under the trade name Delysid) to psychiatrists
in the USA starting in 1949 for their experimental use on
patients.
At the beginning of USA sample distribution, LSD had a
very limited research history, so psychiatrists often tested the
experimental drug in any patient group that intrigued them. In
doing so, psychiatrists were acting as though LSD was a
marketed drug with demonstrated safety that they were just
using off-label for untested indications in patients they wished
to help. The breadth of psychiatric hypotheses to which the
unique properties of LSD were applied at that time included
the following: as an aid in the treatment of schizophrenia; as a
means of creating a Bmodel psychosis^; as a direct antidepres-
sant; and as an adjunct to psychotherapy.
Experimental applications of LSD
Relation of LSD to psychosis
In order to appreciate why LSD was investigated in relation to
schizophrenia, it is instructive to read the drug label written by
Sandoz that accompanied investigational samples of LSD
(Hofmann 1983):
Indications and dosage
(a) Analytical psychotherapy, to elicit release of repressed
material and provide mental relaxation, particularly in
anxiety states and obsessional neuroses. The initial dose
is 25 μg(1/4ofanampouleor1tablet).Thisdoseis
increased at each treatment by 25 μg until the optimum
dose (usually between 50 and 200 μg) is found. The
individual treatments are best given at intervals of
1week.
(b) Experimental studies on the nature of psychoses:Bytak-
ing Delysid himself, the psychiatrist is able to gain an
insight into the world of ideas and sensations of mental
patients. Delysid can also be used to induce model psy-
choses of short duration in normal subjects, thus facili-
tating studies on the pathogenesis of mental disease. In
normal subjects, doses of 25 to 75 μgregenerallysuffi-
cient to produce a hallucinatory psychosis (on an average
1μg/kg body weight). In certain forms of psychosis and
in chronic alcoholism, higher doses are necessary (2 to
4μg/kg body weight).
592 Psychopharmacology (2018) 235:591604
Both of these indications were studied with great enthusi-
asm by psychiatrists with little else available to treat psychosis
or to understand the condition. Given that over 1000 papers
had been published on the effects of LSD in humans by 1963,
it is not simple to determine how well the study designs and
treatment of subjects comported with current standards of
protecting patient safety. However, focusing on evidence from
key clinical researchers with LSD provides insight into what
wasdeemedtobeacceptableatthattime.
Aid in treatment of schizophrenia
The first paper published in English with LSD was in 1950,
reporting on a human study conducted by St. Louis psychiatrists
Anthony Busch and Warren Johnson (Busch and Johnson 1950).
They recounted that they had been looking for a drug that could
exogenously induce a Btransitory delirious state,^after observing
that patients who were experiencing an endogenous Btoxic
delirium^could participate more easily in psychoanalysis.
During this search, the authors report that, BSandoz Company
called to our attention and made available d-lysergic acid
diethylamide.^The report describes the responses of 29 patients,
most of whom were diagnosed with schizophrenia. The dose of
LSD ranged from 300 μg(women)to400μg (men). These doses
are far beyond those recommended by Sandoz. (For context, the
typical recreational dose of LSD ranges from 50 to 250 μg). In the
published paper, no safety procedures are given. No information
is provided regarding the preparation of subjects, the method of
selecting doses, or the means of evaluating changes following
LSD exposure. Using their clinical judgment, the authors con-
clude that LSD Bre-activates anxiety and fear with apparently just
enough euphoria to permit recall of the provoking experiences.^
Although LSD was given with therapeutic intent to patients
with psychosis through the 1960s, there is little evidence that
it produced beneficial results. As Canadian psychiatrist and
LSD researcher Abram Hoffer observed in 1970, BLSD ought
to make people with schizophrenia much worse. It does, in
fact, do so.^(Hoffer 1970).
BModel psychosis^
The ability of hallucinogens to produce a Bmodel psychosis^was
first observed in 1927 by the German psychiatrist Kurt Beringer,
who coined the term in relation to the experimental effects of the
hallucinogen, mescaline (Beringer 1927). One of the first papers
in English on this topic reported in 1952 that LSD produced
Bpsychotic phenomena^in healthy individuals (Rinkel et al.
1952). The prospect that LSD was Bpsychotomimetic^(could
produce psychotic-like responses) was of great interest to scien-
tists. As noted by the psychiatrist and LSD researcher Daniel
Freedman in 1970, BOne of the great inducements of such re-
search was the hope that if one could chemically induce a grossly
altered behavioral state, then clues might be gathered about where
to look in nature for the biochemical factors of clinical disease
(such as schizophrenia) which resemble, but are not identical to,
the LSD state^(Freedman 1970).
However, as Nobel-prize winning biochemist Julius
Axelrod observed, BThe first problem I worked on was the
metabolism of LSD, [which] at that time in psychiatry was
very fashionable. They thought this would give you the clue to
schizophrenia, but a very astute psychiatric nurse can tell the
difference between anybody who took LSD and amphet-
amine, because LSD doesnt resemble schizophrenia at all
but amphetamine does^(Axelrod 2003).
By 1956, Canadian psychiatrist and LSD researcher
Humphrey Osmond concluded that LSD needed to be
reframed away from its association with the induction of mad-
ness. He then created the new term Bpsychedelic^(meaning
Bmind-manifesting^), to replace Bhallucinogen,^which he felt
conveyed that LSD produced a hallucinatory state of psycho-
sis (Novak 2004). (This paper uses the term Bhallucinogen^
because it is the regulatory classification used in the
Controlled Substances Act of 1970; CSA)
Antidepressant and adjunct to psychotherapy
LSD was proposed as a direct daily pharmacotherapy for de-
pression by Swiss psychiatrist Gion Condrau in 1949. This
form of LSD treatment was proposed without counseling,
based on the ability of the drug to produce mood elevation
through euphoria (Hagenbach and Werthmuller 2011). This
LSD regimen did not produce the desired antidepressant re-
sults, however. Even Hofmann concluded that BLSD does not
act as a true medicament; rather it plays the role of a medicinal
aid in the context of psychoanalytic and psychotherapeutic
treatment^(Hagenbach and Werthmuller 2011).
In the period spanning the 1930s to 1960s, numerous drugs
were proposed as Badjuncts to psychotherapy,^including
stimulants (Pohlman 1957), barbiturates (Lehmann 1993),
and benzodiazepines (Tone 2009). Thus, it is not surprising
that LSD was similarly proposed as an adjunct to psychother-
apy, based on its unusual psychological effects, as shown in an
exchange between psychiatrists and LSD researchers Albert
Kurland and Sol Kramer in 1967 (Kurland and Unger 1967):
Kurland: We definitely do not see LSD being utilized
here as a medication in the usual sense. Rather, it is
conceived of as an activating mechanism that brings
about a unique experience ... upon which the therapeutic
intent and structuring is focused...
Kramer: The way I interpret this [is] that it is the psy-
chedelic experience, and not the LSD pharmacology per
se, which produces the antidepressant effect.
There were two sequential approaches to psychotherapy
with LSD: Bpsycholytic^and Bpsychedelic.^As described
Psychopharmacology (2018) 235:591604 593
by Faillace (1966), psycholytic therapy administered 50
200 μg of LSD to patients once or twice a week prior to
therapy, for a duration up to several months, with all sessions
conducted in a special area of a hospital. Although the effects
of LSD can last up to 1216 h, psycholytic sessions lasted
only 48 h because they were attenuated with either a barbi-
turate or an antipsychotic such as chlorpromazine. In contrast,
psychedelic therapy was conducted differently, with patients
undergoing daily psychotherapy for weeks prior to a single
administration of 400 μg of LSD in the same special hospital
setting. During a psychedelic session, the ability of LSD to
Babolish the distinctions between... self and world^was
thought to produce Ban overwhelming transcendental
experience.^The session continued for the full duration of
the effects of LSD, guided by a Bspecially trained^therapist
who was able to guide Bthe intensive reaction... in a very short
period of time.^The LSD session was often followed by more
psychotherapy to integrate the experience.
These two therapeutic approaches are consistent with both
Bsecond force^(psychoanalytic) psychology and Bthird force^
(humanistic) psychology perspectives, which emphasize Bthe
unconscious^and/or Bself-actualization^and identity (Goble
1970). These perspectives stand in contrast to Bfirst force^
psychology (behaviorism), which focuses on observable be-
havior, not thoughts and feelings. While scientific research
from a behaviorist perspective is centered on quantifiable data,
psychoanalytic and humanistic perspectives on research con-
sider psychological meaning and purpose to be paramount.
The contrast between these orientations to research (the pri-
macy of data vs. the production of meaningful experiences)
underlies the difficulties that LSD investigators underwent as
regulations were strengthened.
Regulations to protect subject safety and scientific
integrity
The regulation of human drug research, as elaborated by FDA
and the International Conference on Harmonisation (ICH) un-
der Bgood clinical practice,^has two primary goals (FDA/ICH
2015). The first goal is to assure that the rights, safety, and
well-being of study subjects are protected, consistent with the
ethical principles of the Declaration of Helsinki. The second
goal is to confirm that the study design is scientifically appro-
priate, in order to produce scientifically valid data. In the ab-
sence of adequate study methodology, the risk in exposing the
subject to an unapproved drug cannot ethically be justified.
Since the beginning of the 1900s, the medical establish-
ment in the USA had been discussing how best to protect
the safety of individuals who participate in scientific research.
One advance was a 1935 Supreme Court case that made a
legal distinction between scientific investigations and medical
malpractice, as long as the study design did not Bvary too
radically^from Baccepted methods^and that the patient
provided consent (Fortner v. Koch 1935). Although the 1938
FDCA established that FDA needed to determine that a drug
was safe before it could be marketed, it did not require animal
toxicity testing prior to human experimentation and it did not
specifically address the safety of subjects who participated in
research.
Beginning in 1958, Congress began to hold hearings that
eventually focused on the quality of drug company-sponsored
clinical studies (especially because companies justified high
drug prices on the basis of the high cost of research). These
concerns culminated in the 1962 Kefauver-Harris Amendments
to the FDCA (which took effect in February 1963).
The primary advance of the 1962 Amendments was estab-
lishing that FDA needed to determine that a drug was not only
safe before marketing, but that it was also effective for a spe-
cific medical indication. Prior to this, the Befficacy^of a drug
was determined by the clinical judgment of a physician treating
an individual patient. The AMA stood against the 1962 law,
stating that Bthe only possible final determination as to the
efficacy and ultimate use of a drug is the extensive clinical
use of that drug by large numbers of the medical profession
over a long period of time^(Green and Podolsky 2012).
Robert Temple, the current Deputy Center Director for
Clinical Science at FDA, has stated that the agency could have
interpreted the 1938 FDCA safety regulations as support for
the need for efficacy, based on a risk/benefit analysis (Temple
2011). But in practicality, the need for a company to demon-
strate drug efficacy was only applied selectively prior to 1963.
In addition to efficacy, the 1962 Amendments established that
all premarketing drug studies with humans (whether in pa-
tients or Bnormal controls^) needed to be conducted under
an IND.
Notably, the 1938 FDCA prohibits the distribution of drugs
that are adulterated or Bmisbranded^(have a label that is false or
misleading) into interstate commerce. This means that an NDA
is not only a compilation of all nonclinical and clinical scientific
data to support the marketing of a drugit is also an application
to allow for interstate transport of the drug. The 1938 FDCA
provides a mechanism so that unapproved drugs (such as drug
samples) can be transported across state lines for research pur-
poses without violating the law. This is called a BNotice of
Claimed Investigational Exemption for a New Drug,^which
is actually the legal name for an IND (Junod 2008).
To stop toxic drugs (like thalidomide) from being distrib-
uted anymore as samples, the 1962 Amendments allowed in-
terstate delivery of investigational drugs only if the nonclinical
safety testing data submitted to FDA was adequate to justify
the initiation of drug use in humans. Under an IND, investi-
gators also had to agree not to share the drug with other in-
vestigators (Junod 2008).
The IND process is separated into Phase 1 studies (with
healthy volunteers to evaluate safety) and Phase 2 and 3
594 Psychopharmacology (2018) 235:591604
studies (with patients to evaluate safety and efficacy). At the
end of research, all nonclinical and clinical study data and
study protocols are compiled to create the NDA. An NDA is
submitted to FDA when a sponsor believes it can demonstrate
the safety and efficacy of a drug for a particular indication at
specific doses.
Given that LSD has never been a marketed pharmaceutical
with an FDA-approved NDA, this paper will focus on the
methodology of clinical studies conducted under an IND with
LSD before and after the 1962 Amendments.
These new regulations were needed because, as FDAs
Frances Kelsey reported, Bmany clinical trials were poorly
performed [prior to 1962] .... I was quite shocked at the caliber
of the work that had gone into the applications in support of
safety^(Kelsey 2014). While the IND requirements were ex-
tensive (see below), they were vague about how a researcher
might fulfill each aspect in practicality.
This meant that FDA reviewers were left to interpret what
specific kind and amount of information drug companies or
investigators needed to provide in order for a clinical study to
proceed under an IND. Coming out of the 1950s, high-level
FDA officials were typically former inspectors who did not
have medical or scientific degrees (Hilts 2003). At the review-
er level, FDA did employ some physicians, but Bthey kept up
their private practice and [were at] their FDA desks only part-
time^(Hilts 2003). (FDA subsequently hired qualified scien-
tists and physicians.) Prior to the 1962 law, there was often a
much-too-friendly tone taken between drug companies and
FDA. As Frances Kelsey recalled, BIt was very common for
reviewers... to go out to lunch at fancy restaurants with the
drug firm representatives. There was an end to that by the time
I came [in 1960], but I still used to hear tales of eating at the
Rive Gauche^(Kelsey 2014).
The requirements of an IND, as described in Part 312 of the
Code of Federal Regulations (CFR; 21 CFR 312), include in-
formation regarding: the drugs chemistry and manufacturing,
animal toxicology, the proposed clinical study protocol, and the
qualifications of the investigator and research facility.
Additionally, investigators had to commit to personally conduct
or supervise the study procedures, and provide timely submis-
sion of adverse event (AE) reports. Other requirements were
added in 1963 for signed informed consent from subjects and in
1966 for independent subject safety oversight by an IRB.
After the IND requirements had taken effect in 1963, many
investigators who had been administering LSD to patients did
not feel it was necessary to Bprove^to FDA that LSD was
reasonably safe in order for them to continue running human
studies. As the FDA reported following a 1964 visit to psy-
chiatrist and LSD researcher Harold Abramson, BHe feels that
he, as a doctor, may administer any drug to his patients in the
course of treatment and that the government hasnt any juris-
diction in the matter.^(Schorr 1964). By this time, there were
hundreds of clinical studies published in the medical literature
reporting that LSD did not produce serious overt physiologi-
cal distress in most humans. Nonetheless, investigator belief
did not satisfy the modern regulatory standard that determined
whether a drug can be deemed Bsafe^for use in clinical trials.
Similarly, Befficacy^of an experimental drug is not deter-
mined by clinical judgment, but instead is based on FDA evalu-
ation of data from Badequate and well-controlled investigations^
(21 CFR 314.126) conducted under an IND. This includes the
following: evaluation of subjects with a specific medical condi-
tion; use of a standardized test drug and control condition; ade-
quate sample size, treatment duration, and treatment design (par-
allel or crossover); randomization of subjects to treatment condi-
tions; blinding; submission of a full protocol; and appropriate
statistical analysis of data. These criteria were affirmed as appro-
priate by FDA in 1970 (35 Fed. Reg. 7250).
Despite what appears to be a specific list of requirements
for an appropriate clinical study, Hilts (2003)reportsthatBit
took more than two decades before the letter of the 1962 law
was being observed,^such that the Bart of clinical trials^was
invented as investigators and regulators went along. A decade
after the 1962 Amendments, the Supreme Court weighed in
on these issues, similarly concluding that Bclinical impres-
sions of practicing physicians and poorly controlled experi-
ments do not constitute an adequate basis for establishing
efficacy... Isolated case reports, random experience, and re-
ports lacking the details which permit scientific evaluation
will not be considered as corroborative support of well-
controlled studies^(Weinberger v. Hynson 1973).
What follows below is a detailing of the various elements
that are necessary to satisfy the requirements of an IND re-
garding appropriately conducted clinical studiesand how
investigators who wished to conduct human studies with
LSD in the 1960s struggled with their fulfillment.
IND: chemistry and standardization of study drug
Gaining access to a standardized experimental compound,
with known chemistry and synthesis, is often the key step in
determining whether a human study can be considered. In the
1960s, access to LSD changed dramatically from what it had
been in the 1950s. This produced a very complicated history,
as described below.
Sandoz submits INDs for LSD
As noted by FDA Commission James Goddard at a 1966
Senate Committee hearing on LSD, Sandoz first made FDA
aware of LSD in 1953, following their distribution of the drug
to European psychiatrists. The purpose of the FDA visit by
Sandoz was Bto discuss clinical investigations Sandoz was
planning to pursue in the United States... The Sandoz repre-
sentatives told us that the great power of this drug contained in
Psychopharmacology (2018) 235:591604 595
very small doses led them to believe it should be available
only to qualified research psychiatrists. Our agency agreed
completely.^
Following the passage of the 1962 Amendments, Sandoz
submitted an IND for LSD in 1963 (Carpenter 2011). As
required, the IND would have included information about
the drugs chemistry and manufacturing with regard to the
standardized ampules and tablets that Sandoz had been dis-
tributing as samples to clinical investigators. This information,
however, was proprietary and therefore not publicly available.
Thus, researchers who wished to continue using LSD in hu-
man studies did not have access to the necessary chemical
information required for submission of their own IND. This
meant that researchers would need to obtain a letter of autho-
rization (LOA) from Sandoz in order to establish a Bright of
reference^to the chemistry data.
Sandoz, however, was not interested in giving LOAs for their
proprietary and patented LSD chemistry to most researchers who
wanted to conduct human studies with LSD. In 1962, Sandoz
had established a committee of trusted investigators to advise on
whether researchers who wanted to test LSD were Bcompetent to
work with the drug^basedonscientificBstandards of practices^
(Buckman 1966). If a researcher did not pass Sandozsmuster,
they would not receive a LOA, and therefore could not get an
IND and gain legal access to Sandoz LSD. This left many re-
searchers who had conducted LSD studies in humans angry and
frustrated, especially after the way Sandoz had freely distributed
the drug previously.
Although precursor chemicals to synthesize LSD were
widely available in 1963 (Hagenbach and Werthmuller
2011), use of LSD from any source other than Sandoz would
have been illegitimate for research purposes at that time be-
cause they were the only entity who had submitted chemistry
information under an IND. Without FDA approval of the drug
source (and drug label used for distribution), any LSD pur-
chased from sources other than Sandoz would have been
Bmisbranded,^a violation of the FDCA.
Illicit sources of LSD for research
Many clinical laboratories ceased LSD research when they
could not obtain the drug legally. Some researchers still had
large supplies of Sandoz LSD, but refrained from using it
without an IND in their own name. This was because, as they
were cautioned by Rudolph Bircher of Sandoz in a 1965 sym-
posium, BYour malpractice insurance, if something should go
wrong, would never cover it.^(Murphy 1967). (It is notable
that Bircher did not appear troubled by use of his companys
experimental drug with patients prior to 1963).
Some investigators who were especially invested in main-
taining their human LSD research sought access to LSD
through illicit sources. Shortly before the Amendments took
effect in 1963, Myron Stolaroff of the International
Foundation for Advanced Study (IFAS) in Menlo Park, CA,
concluded that they might not be able to submit a successful
IND and continue their investigations because of the lack of a
LOA from Sandoz. This meant they would not be able to
legitimately obtain Sandoz LSD. The LOA may not have been
forthcoming because of investigator qualifications. As re-
quired for all drug studies, IFAS did have a physician on staff:
psychiatrist Charles Savage, who would go on to do LSD
research at the National Institute of Mental Health (NIMH)
and Spring Grove State Hospital, near Baltimore, MD (see
below). But some of the other IFAS investigators who were
heavily involved in running the LSD sessions (as if they were
psychotherapists) had no actual mental health credentials.
FDA informed IFAS that, BIn our opinion, the proposed co-
investigators... Alfred M Hubbard and Myron Stolaroff, do
not possess necessary qualifications for undertaking the pro-
posed clinical investigations^(Harvey 1965). This was be-
cause Stolaroff was an engineer (formerly with the electronics
company Ampex) (Walsh and Grob 2005), while Hubbard
was an engineer who had purchased a Bmedical degree^from
a fake university (Lee and Shlain 1985).
Stolaroff decided to make contact with Bernard Roseman
and Bernard Copley, who promised to sell him LSD made by
underground chemists (Roseman v. United States 1966).
When the two men arrived in Menlo Park after a trip to
Canada, they sold two bottles of LSD to Stolaroff for $600
each, as well as a sample of LSD to an undercover federal
agent. The men were arrested, based on violations of the
FDCA (among other laws). Notably, they were not charged
for selling a controlled substance because such laws did not
yet apply to LSD.
In the trial thatfollowed, the men claimed they could not be
prosecuted under the FDCA for misbranding because FDA
had no jurisdiction over LSD that had been synthesized and
sold within the borders of California (in other words, without
interstate commerce). The government disagreed (saying the
drug had been obtained either from Israel as the men had
originally asserted, or from their trip to Canada) and the men
were sentenced to 17 years in jail.
Interestingly, no charges were placed against Stolaroff for
seeking to obtain an experimental drug from an illicit source. It
is likely this occurred because Stolaroff appears to have turned
states witness. According to Tim Scully, a well-known under-
ground LSD chemist, BRoseman believed Al Hubbard had
convinced Myron Stolaroff to turn [him and Copley] in to
the FDA^(Scully 2013). Unbeknownst to Scully, the truth
of his allegations had actually already been confirmed in
1966 when FDA Commissioner Goddard testified about the
Menlo Park case during Senate hearings on LSD. Goddard
stated, BTwo men offered to sell... [LSD] to a [psychothera-
pist]. This man reported the incident to us. One of our agents
contacted the sellers. They came to his house all set to make a
big sale. They were promptly arrested.^(Goddard 1966).
596 Psychopharmacology (2018) 235:591604
As psychiatrist and LSD researcher Abramson stated at a
conference in 1965, BIts virtually prohibited now for a private
physician to use LSD unless his patient buys it on the black
market ... I have had patients who tell me, If you wontgive
me LSD, Ill get it and then come in.Naturally, I disapprove
of this^(Murphy 1967).
Further restriction on access to LSD
In 1965, Congress passed the Drug Abuse Control
Amendments (DACA) to the 1938 FDCA, which allowed
FDA to regulate depressants, stimulants, and hallucinogens.
In 1966, the LSD precursor chemicals lysergic acid and
lysergic acid amide also came under control through this law
(US Bars Distribution 1966). DACAwas passed following the
creation of the Bureau of Drug Abuse Control, an enforcement
arm within FDA that was a precursor to the DEA. This law
prohibited the manufacturing, compounding, processing, or
sale of the cited drug classes unless permitted by the govern-
ment for wholesale distribution, research, or medical applica-
tions (through an IND, for example). This meant that doing
human research with LSD without an active IND would be in
violation of DACA. Although DACA was a precursor to the
1970 CSA (see below) and the 1971 international treaty,
Convention on Psychotropic Substances, it did not penalize
personal use or possession of the listed drug classes.
Sandoz withdraws their IND
By August 1965, Sandoz decided to stop production and dis-
tribution of LSD. This was in part because their patent had
expired in 1963, but also was in consideration of Bthe flood of
requests^for the drug (Hofmann 1983)andtherisinginci-
dence of LSD use for recreational purposes. In their public
statement, they said: BDespite the outstanding properties of
[LSD], or rather because of the very nature of these qualities
... the usual means of practical exploitation could not be en-
visaged. In spite of all our precautions, cases of LSD abuse
have occurred ... completely beyond the control of Sandoz,
[reaching] the scale of a serious threat to public health^
(Hofmann 1983).
In April 1966, Sandoz notified FDA that they wished to
withdraw their IND for LSD. This action was a formalization
of discussions that had already occurred with federal officials,
who had orchestrated a means through which investigators
approved by Sandoz would be allowed to continue LSD re-
search in humans. Under this program, according to Stanley
Yolles, Director of NIMH, the remainder of the Sandoz LSD
supplies in the USAwere delivered to NIMH by armored car
in April 1966 (Yolles 1966). The 21 g of LSD that NIMH then
possessed was estimated to have a street value of $300,000
($2.3 million in 2017 dollars). This amount of LSD was
enough to supply 210,000 doses of 100 μg each to acceptable
laboratories conducting human research.
In newspaper coverage of these events, it was reported that,
BSandoz... regrets that it has to withdraw the investigational
drug applications for LSD and will no longer be able to supply
even qualified medical investigators^(Schumach 1966).
Despite this assertion, Sandoz subsequently provided LOAs
to 17 investigators they deemed acceptable, who were then
able to submit their own INDs and successfully receive LSD
for their clinical experiments (Goddard 1966). According to
FDA Commissioner James Goddard at the 1966 Senate hear-
ings on LSD, Sandoz had decided that their policy for provid-
ing an LOA and for providing LSD would be based on an
investigator having grants or authority from NIMH, the
Vet e r a n s Administration, or state agencies to conduct LSD
research in humans, as long as it occurred in a carefully con-
trolled environment, such as a hospital (Goddard 1966).
Goddard testified, BThere were about 70 projects approved
prior to Sandoz withdrawing from direct support and investiga-
tion of the drug. There are now, I believe, 9, with 12
investigators.^This statement reflects that out of the 17 inves-
tigators who had been given LOAs by Sandoz, a total of 9 INDs
for clinical studies with LSD were submitted and allowed to
proceed by FDA. This meant that these investigators could keep
their current supplies of LSD and apply for additional drug as
necessary in order to complete their studies. Sandoz supplied
the LSD in ampules that contained a 100 μg/ml solution of
LSD, as well as in tablets that contained 25 μgofLSD
(Hollister 1968). However, as Frances Kelsey testified at the
1966 Senate hearings, if a Sandoz LOA was not obtained, Ball
the investigators listed in that IND were required to stop their
studies and turn back their LSD^(Kelsey 1966). Eventually,
Sandoz extended their right of reference to grantees of Bother
approved national agencies^such as the National Science
Foundation, expanding the number of INDs submitted by qual-
ified investigators to 53. It is not possible to determine from
public records whether these INDs were primarily submitted
from investigators who had previously worked with LSD or
were instead from new investigators. However, all proposals
for new clinical studies with LSD underwent Bdual review^
by both NIMH and FDA (Goddard 1966).
FDA-PHS psychotomimetic advisory committee
In 1967, NIMH separated from the National Institutes of
Health (NIH) to become its own bureau in the Public Health
Service (PHS), with status equivalent to that of NIH (NIH
Almanac, 2016). That same year, the FDA-PHS
Psychotomimetic Agents Advisory Committee (PAAC) was
formally established with representatives from FDA, NIMH,
and up to 12 nongovernmental mental health and pharmacol-
ogy professionals (US Makes LSD More Available 1968). The
PAAC met six times a year and determined whether proposed
Psychopharmacology (2018) 235:591604 597
animal and human studies with hallucinogens and cannabis
were scientifically valid and whether investigators would be
allowed to access study drugs from NIMH supplies.
1
The PAAC was put in place in 1967 specifically to expedite
the processing of study applications compared to the old sys-
tem. According to psychiatrist Kurland at Spring Grove State
Hospital, BIt isnttoodifficulttodoresearchinthisareaifyou
submit a protocolIf [the studies] meet the judgment of your
scientific peers, they will be approved. Whether it will be
funded is another matter^(Debold and Leaf 1967).
IND: scientif ically designed clinical studies
In the USA, the federal government was heavily involved in
funding clinical scientific studies with LSD. According to the
1966 Senate hearings on LSD, Kurland was provided with
large multi-year grant funding from NIMH for his LSD stud-
ies with alcoholics ($142,056 from 1964 to 1967) and with
neurotics ($309,472 from 1965 to 1968). In general, NIMH-
funded clinical studies with LSD in the 1960s tested a limited
number of subjects, used patients with loosely diagnosed psy-
chiatric disorders (or they accepted patients with a wide vari-
ety of disorders), and often did not use a valid control condi-
tion (which prevented both the randomization of subjects into
groups based on a parallel or crossover design, as well as the
ability to conduct a statistical analysis).
Thus, none of the NIMH-funded clinical studies with LSD
from any laboratory qualified as Badequate and well-
controlled^for evaluating safety and efficacy at the level ex-
pected for studies submitted in an NDA. Therefore, these hu-
man studies are best characterized as either hypothesis-
generating individual case reports or as small pilot studies.
Even Sandoz never conducted systematic Phase 1 safety stud-
ies or sufficiently large Phase 2 and 3 efficacy studies to de-
termine whether specific doses of LSD administered to a pa-
tient population with a particular medical condition produced
statistically significant changes compared to placebo on stan-
dardized outcome measures.
This means that it is difficult to discern the strength of the
safety signals or evaluate evidence of efficacy from these early
published clinical studies with LSD. In part, this is because the
standards for scientific reporting on clinical studies were often
much less rigorous than they are today and relied heavily on
the judgment of the clinical investigators (rather than on val-
idated outcome measures). Additionally, as mentioned above,
the standards for all drug research at that time were poorly
defined or enforced. Thus, these scientific issues were not
isolated to clinical research with hallucinogens or psychiatric
conditions in general.
Given the limitations of evaluating human LSD study pro-
cedures as published in the medical literature in the 1960s, it
would be ideal to be able to directly analyze the original clin-
ical protocols as submitted in an IND. Unfortunately, out of all
the INDs for human studies with hallucinogens that were sub-
mitted to FDA in the decade immediately following the 1962
Amendments, only a few are still readily available for scrutiny
internally by FDA personnel. Additionally, all information
submitted under an IND is held as confidential and FDA can-
not even disclose the existence of an IND unless it had been
publicly acknowledged (21 CFR 312.130). Although individ-
uals can request information under the Freedom of
Information Act (FOIA), FDA can only make a disclosure
determination regarding which information from an IND is
releasable when it processes the FOIA request. There are ad-
ditional challenges to FDAsdisclosureevaluationwhenthe
principle investigator is dead or an institution has dissolved.
Based on these limitations, it is not possible to publicly
present specific information from a clinical study with LSD
that is only available through an IND submitted to FDA. This
is unfortunate, since the information contained in the INDs for
LSD that are available internally at FDA creates a riveting
narrative about the investigators and regulators as they nego-
tiate on the clinical studies. However, it is possible to deduce
from publicly available information whether an investigator
had an IND. For example, as described above, it is known
from the 1966 Senate record that Kurland received extensive
NIMH funding in the mid-to-late 1960s for his LSD studies in
alcoholics and neurotics. This means that he was eligible to
obtain a LOA from Sandoz in order to receive LSD. He sub-
sequently published numerous clinical studies with LSD in the
scientific literature. Since he could not have legally conducted
these investigations after 1963 in the absence of an IND, it is
clear that FDA must have allowed his studies to proceed under
an IND, based on submission of an LOA from Sandoz. Thus,
it is instructive to evaluate his publications in terms of how
well his studies conform with the 1938 and 1962 FDA regu-
lations in light of current scientific standards.
Animal toxicology testing
Currently FDA does not allow clinical studies to begin until a
test drug has undergone sufficient animal toxicity testing to
predict that the drug can be safely administered to humans.
However, in the years immediately after the 1962
Amendments, the degree of nonclinical toxicology necessary
before clinical studies under an IND were allowed to proceed
was variable.
1
This system will be familiar to any current cannabis researcher whose non-
NIH funded study protocol was required to go before a modern version of the
PHS committee in order to obtain botanical marijuana from the National
Institute on Drug Abuse (NIDA). (NIDA was originally founded in 1973
within NIMH, after it had rejoined NIH). This modern iteration of the PHS
committee had representatives from NIDA and FDA, but was abolished in
2015 in a federal effort to streamline marijuana research.
598 Psychopharmacology (2018) 235:591604
Starting in the 1950s, Sandoz had extensively distributed
samples of LSD, despite the lack of extensive nonclinical data
demonstrating that the drug was not toxic. During FDA eval-
uation of the Sandoz IND for LSD in 1963, the agency initial-
ly considered terminating the IND, since the company had
submitted very limited animal toxicology data (DAguanno
1963). However, agency reviewers argued that there was al-
ready extensive clinical experience with the drug. Given that
these studies suggested the possibility of efficacy without se-
rious AEs or deaths, the Sandoz IND was supported by FDA.
In retrospect, it is interesting that the Sandoz IND had a pau-
city of nonclinical toxicity data for LSD, given that FDA only
allowed other investigator-led clinical studies with LSD to
proceed if they had right of reference (through an LOA) to
the animal data in the Sandoz INDor they had generated
their own animal toxicity data.
At FDA, Kelsey was hesitant on the clinical use of LSD
because of the dearth of data from animal reproductive toxicol-
ogy studies. She was no doubt sensitized by her experience
with thalidomide, especially when allegations emerged of chro-
mosome damage resulting from LSD use. In March 1968,
Kelsey was quoted in the Wilmington Morning News
(Delaware) that Bno definite causal relationship has been
established [between LSD and chromosomal changes]^,but
that FDA was testing pregnant monkeys with LSD (FDA
Aide Links LSD 1968).
As described by psychologist and LSD researcher William
Richards (2015), an evaluation of reproductive toxicity from
LSD was conducted in 1969 by his research team in Kurlands
laboratory at Spring Grove State Hospital. They used a dou-
ble-blind, FDA-approved study protocol (in collaboration
with NIH) that tested blood from 32 subjects before and after
LSD psychotherapy (Tjio et al. 1969a). Their study showed
Bthere is no definite evidence that pure LSD damages chro-
mosomes of human lymphocytes in vivo^.Itislikelythatthis
study, as well as similar studies and reviews (Tijo et al. 1969b;
Long 1972; Dishotsky et al. 1971) were instructive in the
decision of FDA to allow LSD research to continue. To date,
there are no credible data supporting the allegation that LSD
alters genetic material.
A controlled study of LSD therapy with alcoholics
Kurlands group published two papers based on their study
evaluating LSD as an adjunct to psychotherapy with a large
number of alcoholics: a preliminary report in 1967 with 69
patients (Kurland et al. 1967) and a final report in 1971 with
135 patients (Kurland et al. 1971).
According to the published papers, the alcoholic patients
first received intensive psychotherapy Bnearly every day^for
2 weeks, for a total of 1220 h with a Bspecially trained^
therapist. Once Bthe quality of the therapeutic relationship
[had] opened,^the LSD session was scheduled. The protocol
specifies that the study uses a Bpsychedelic procedure,^in
which the patient would receive LSD at either 450 μg(thetest
drug condition) or 50 μg (as the active control condition) in a
double-blind design. In a latter phase of the study, some pa-
tients were allowed to receive up to two additional LSD ses-
sions if they participated in 6 months of outpatient therapy.
During an LSD session, the patient was extensively moni-
tored by the therapist and a nurse for 1012 h, while listening
to music in a Bcomfortable living room^setting at the hospital
while wearing eyeshades or interacting with the therapist.
Patients received Ba heavy dose of tender loving care,^which
the researchers believed was Ba highly significant ingredient
in the mobilization of psychedelic reactions.^The study eval-
uated changes in the patients before and after LSD sessions
using 12 psychological tests that measured personality,
Bintelligence functioning and impairment^.
LSD produced improvements in those individuals who re-
ceived either the treatment dose (450 μg) or the active control
dose (50 μg). Undefined evaluations of Bdrinking behavior^
showed improvement in 121 of 135 patients who were avail-
able for follow-up in both LSD groups, but the degree of
change, as well as baseline drinking to qualify subjects as
alcoholic, were not provided. This was reported as being sta-
tistically greater in the high dose group at 6 months. But by 12
and 18 months after treatment, there were statistically similar
high degrees of improvement in average Bdrinking behavior^
for individuals in both LSD groups. With regard to safety, the
paper reports that Bonly one adverse reaction^was reported by
any of the 135 patients who received LSD, but that AE and its
management are not described. This strongly suggests that
clinical judgment, rather than use of a list of AEs that occur
commonly or rarely in clinical studies, determined if a men-
tionable AE had occurred.
Choice of control condition and blinding
The Kurland alcoholic study raises the issue of the value of an
active control compared to (and especially in lieu of) a placebo
control. One purpose of a control condition, in combination
with blinding, is to reduce possible bias by both subjects and
investigators regarding the impact of treatment. Yet as ob-
served by psychologist Richard Yensen (who later joined
Kurlands group as an investigator), BDouble-blind controlled
studies have been demonstrated to be an inappropriate meth-
odology for studying LSD, because it is not feasible to create
an effective blind for LSD with either an active or inactive
placebo^(Yensen and Dryer 1992).
Although controlling bias is important, a more important
scientific purpose of a control group is to determine whether
changes in outcome measures during a study can be attributed
to the experimental treatment, or rather to other factors (FDA
2001). This is why most modern psychiatric drug studies only
evaluate behavioral or psychological changes produced by the
Psychopharmacology (2018) 235:591604 599
test drug in comparison to a neutral placeboeven when the
test drug produces AEs (such as anticholinergic effects or
sedation) that easily distinguish active from inactive treat-
ment. Placebo controls have been the gold standard in clinical
studies since the 1950s (Shorter 2011).
In Kurlands study with alcoholics, both doses of LSD (the
threshold dose and the psychedelic dose), in conjunction with
psychotherapy, reduced Bdrinking behavior^1218 months
after drug treatment. However, by not including a placebo
condition, it is not possible to determine whether LSD is effi-
cacious in reducing drinking no matter what dose was given
(even barely noticeable ones), or whether LSD had no effect at
all and the long-term positive responses are attributable to the
intensive therapy. Thus, it cannot be determined whether LSD
was better than no drug treatment, even though the blinding of
the investigators and subjects was managed.
Informed consent
As early as the 1950s, researchers recognized that adequately
informing a potential subject about an LSD study would be
difficult, given the individualized responses produced by the
drug. There were two schools of thought at that time on the
question of whether, or how, to obtain consent for study par-
ticipation. On the one hand, many patients who received LSD
in that era were told that theywere receiving a novel treatment,
but not that they were participating in research. The identifi-
cation of the drug as LSD might not be conveyed to patients
or it could be the only information conveyed, without details
of its effects (Abramson 1967).
For example, when LSD was tested in schizophrenic pa-
tients for ostensibly therapeutic purposes, the patients were
unlikely to be informed that the drug might exacerbate their
psychotic symptoms. In psychologist Betty Eisnersmemoire
of her work with hallucinogens (Eisner 2002), she recounts
how a patient was Bon the verge of a psychotic episode.^
Despite concerns that LSD treatment could Bblow him into a
paranoid schizophrenic psychosis,^the team physician decid-
ed that since the patient was Bheading in that direction
anyway,^Btheres nothing lost if we try.^Similarly, when
LSD was being given to opioid-addicted prisoners at the
Addiction Research Center in Lexington, KY, to evaluate its
psychoactive effects, the subjects were not usually informed
about what they were receiving or what to expect. This likely
accounts for the reason why the BLSD^scale on the Addiction
Research Center Inventory (ARCI) of subjective responses to
drugs represents Bdysphoria^responses.
On the other hand, for those who believed LSD might have
a valuable role in psychotherapy, providing some knowledge
about the drug effects was part of the proper preparation of a
subject so that the LSD session would be beneficial. This is
known as the Bset and setting^for an LSD session, referring to
the mindset of patients and the environment in which they
would experience the drug. As observed by Yensen and
Dryer (1992), the degree of enthusiasm of the investigator
was often recognized to influence the therapeutic outcome
from LSD treatment.
After the 1962 Amendments took effect in 1963, investiga-
tors were required to obtain written informed consent from sub-
jects prior to their participation in a study. However, the concept
of consent with LSD is complicated when the investigator can-
not predict how any particular person will respond to the drug.
Investigators might also produce an Bundue suggestive effect^
that can adversely affect the therapy (Barrigar 1964).
According to Kurlands published papers, the study patient
was given an Binformational and expectation-structuring^
packet of articles about LSD treatment. He was informed of
the study procedures and the effects of LSD, including possi-
ble Balarming reactions^and other general AEs. (The patient
was always a man because FDA policy in the years immedi-
ately after 1963 did not allow women of childbearing age to
participate in drug studies, based on fears of teratogenicity in
the wake of the thalidomide crisis (FDA 2017)). Kurland ac-
knowledged that in the early days, informed consent Bwasnt
as elaborate as [it was] later^(Kurland 1997). This would be
consistent with many consent documents of this era that do not
contain genuine safety information for the potential subject to
consideror inform the patient that the test drug was investi-
gational. Instead, the text often appears to be primarily in
service of releasing the research unit of legal responsibility
for AEs (Campbell and Stark 2015).
Use of LSD by investigators
In 1966, FDA Commissioner Goddard testified at the Senate
hearing on LSD that, BReports of nonmedical use of LSD [by
investigators] had come to FDA as early as 1961.^This prac-
tice was surely enhanced by the Sandoz drug label for LSD,
which explicitly encouraged investigators to test the drug on
themselves so they would be familiar with its effects.
In 1969, Kurlands group initiated a program in which
mental health professionals would be allowed to receive one
to three LSD sessions in order to better understand uncon-
scious processes and improve their own therapeutic skills
and empathy (Yensen and Dryer 1992). In an oral history,
Kurland recalled that some on the Spring Grove staff wanted
to be exposed to LSD so that it might Benhance [their] capacity
for interacting^with patients (Kurland 1997). Kurland told
them this would be run scientifically, saying, BBefore anybody
gets involved, were going to have some rules. The rules are,
you have to go through a procedure just like the patient. You
have to be interviewed by a number of psychiatrists.^All told,
according to Yensen and Dryer (1992), B203 professionals
received one to three LSD sessions in this program between
1969 and 1976^at Spring Grove. Many of these individuals
reported Bconsiderable benefits from their LSD sessions^.
600 Psychopharmacology (2018) 235:591604
Self-experimentation outside of regulated studies was also
common at this time. Prior to joining Spring Grove, psychol-
ogist Sanford Unger was at NIMH and took LSD while there,
along with his section chief and the director of clinical inves-
tigation (Neill 1987). Unger later said, BIt seems necessary,
unfortunately, in 1968, to say at the time, 1962, it seemed not
only logical or desirable, but even a respectable course of
action^to try LSD (Unger 1969).
Conclusions
For over 70 years, scientists have been fascinated with the
unique pharmacological and psychological effects of LSD
and other hallucinogens, as well as their potential therapeutic
applications. Currently, when INDs are submitted to FDA for
human studies with hallucinogens, they are evaluated accord-
ing to a variety of regulations dating back to the turn of the last
century. These regulations are the same ones that govern all
drug research and are applied in a neutral fashion, even for a
drug class like hallucinogens that carries cultural baggage.
The bottom line for FDA in determining whether a study
may proceed is based on whether the studies are designed
and conducted in a manner that protects subject safety and
will produce valid scientific data that justifies the risk to the
subject.
There is no doubt that complying with myriad rules and
regulations can be time-consuming and frustrating for an in-
vestigator who wishes to conduct a clinical drug study. But the
reason these regulations were developed over time was not to
delay the ability to initiate research. Regulations were
established to prevent the exploitation of human beings for
intellectual curiosity, unethical financial gain, or worse.
Since the 1960s, many other regulations have been put in
place, including ones ensuring study subject Brights and
welfare^through IRB oversight, as well as restrictions on
research with children, prisoners, and other vulnerable popu-
lations. These regulations are in place to assure that human
rights are upheld during clinical research and that the experi-
ments will produce scientifically valid data.
Although the 1962 Amendments to the 1938 FDCA listed
specific methodology required for human drug studies, these
were not immediately adopted by most clinical sites in the
way we understand them now, regardless of the type of drug
being investigated. When the published clinical studies with
LSD in alcoholics from Albert Kurlands group at Spring
Grove State Hospital are examined, it is clear they are among
the best of that era in that they attempted to conform to the
regulations for Badequate and well-controlled^studies.
However, by modern standards, his published study reports
do not provide information on the amount of alcohol con-
sumption used to qualify subjects, or on randomization, in-
formed consent, IRB approval, monitoring and management
of AEs, justification of outcome measures, amount of drinking
after treatment, and statistical evaluation of data.
Although we may wish to presume that all research groups
that were allowed by FDA to conduct hallucinogen research
were as scientifically dedicated as Kurlands, much of the
hallucinogen research in this period falls short of ideal scien-
tific methodology. This is not a modern observation, however.
There were many published reports in the years following the
1962 Amendments that criticized the general scientific integ-
rity of the ongoing LSD studies, including from hallucinogen
investigators at NIMH and Spring Grove:
&Jonathan Cole (NIMH): BWe must stress that none of these
claims [for LSD] are based on detailed, carefully con-
trolled studies. None of [the hallucinogens] have been
proved to be effective or safe therapies for any psychiatric
condition.^(Cole and Katz 1964)
&Sanford Unger (NIMH and Spring Grove): BNot a single,
methodologically-acceptable controlled study of the effi-
cacy of LSD-assisted psychotherapy has yet been per-
formed. The many claims of dramatic therapeutic chang-
es... must thus be regarded as not proven.^(Unger 1964)
&Charles Savage (Spring Grove): BNearly all studies [with
hallucinogens] have serious shortcomings... [which] in-
clude: 1. anecdotal evidence; 2. inadequate assessment
procedures; 3. insufficient follow-up; 4. naive statistical
treatment; 5. lack of controls.^(Savage et al. 1967)
These critiques demonstrate why it is not possible to extrap-
olate clear conclusions from these older studies about the safe-
ty and efficacy of LSD for any particular disorder. Instead, the
data from these studies suggest possible psychiatric applica-
tions of hallucinogens, which may produce hypotheses that can
be subjected to modern scientific evaluation through appropri-
ate regulatory oversight. Such clinical studies have begun, but
most of them are still in the small-scale, pilot study phase.
There is a common narrative among those who follow the
history of psychedelic research that all clinical studies in the
USA with this class of drugs terminated in 1976 and did not
recur again until Rick Strassman began his dimethyltrypta-
mine (DMT) clinical investigations in 1990. Although it is
true that human hallucinogen research in the USA decreased
dramatically after the 1960s, Yensen and Dryer (1992)report
that investigators who had been associated with Spring Grove
(by then renamed the Maryland Psychiatric Research Center)
continued to administer LSD to patients with anxiety and de-
pressive disorders under an IND until 1987.
So what brought about the severe reduction in hallucinogen
studies in humans in the 1960s and 1970s? Surely the societal
impact of the recreational use of LSD played a role, in terms of
how Sandoz, the government, and even researchers distanced
themselves from the bad perceptions associated by some with
hallucinogens. But as this paper details, the inability of
Psychopharmacology (2018) 235:591604 601
researchers to comply with the new regulations often
prevented study initiation. It is also likely that other regulatory
issues also played a critical role.
FDA had strongly encouraged Sandoz in the 1950s Bto
think seriously about submitting [an NDA] as soon as
possible^(Goddard 1966). By 1965, FDAs Kelsey fretted
that clinical investigations with LSD Bcould not go on indef-
initely without some attempt at obtaining an approved NDA^
(Kelsey et al. 1965). Otherwise, the experimental drug effec-
tively would be available to research psychiatrists as if it were
a legally marketed drug, which is exactly what the 1962
Amendments sought to curtail. FDA proposed that they might
consider giving an Beffective NDA under very restrictive
labeling^, but Sandoz rejected the idea, stating that they were
not considering the submission of any NDA (Kelsey et al.
1965). No other drug company stepped forward to take up
the task of drug development for LSD, so the clinical studies
conducted with the drug remained small and inconclusive (as
is the case for any investigator-led drug study). This contrib-
uted to NIMH closing down their intramural (in-house) hu-
man research with LSD in 1968 (Oakley and Ksir 1999).
Then, in 1970, the U.S. Congress placed LSD into
Schedule I of the CSA, indicating that the drug had high abuse
potential and no currently accepted medical use, except for
research. This created additional requirements for researchers
who wished to conduct clinical studies with LSD, including
the need to obtain a Schedule I license from DEA for each
individual study. Under the CSA, the protocols and
investigator/study site adequacy for these studies were evalu-
ated not only by DEA, but by FDA, prior to the approval of
the license (and separate from the IND system). Since DEA
had no mandated time frame for responding to an applicant, a
study could bein limbo for a long duration with little ability to
prompt a response. Similarly, if FDA refused to let a clinical
study with LSD proceed within the 30-day clock after initial
submission of an IND, there was no mandated time frame with
which FDA needed to resolve these concerns after an appli-
cant provided additional information. Thus, the slow review
time of INDs and Schedule I licenses by government agencies
could prevent the initiation of a human study with LSD for
long periods of time. Even though some clinical research with
LSD was still proceeding, other tenacious researchers were
surely frustrated by the time lag, which likely led to a decrease
in the number of laboratories willing to engage in the regula-
tory endeavor.
On top of this, access to LSD was still largely limited to
those laboratories that had successfully received funding from
an NIMH grant after competing with other proposals for the
experimental treatment of psychological disorders. By 1973,
NIMH had spent 20 years and up to $7.5 million funding
research with 2500 individuals who participated as subjects
in 116 clinical studies with LSD (Asher 1975; Pollan 2015).
However, NIMH had little to show for their two decades of
investment in terms of progress towards an approved drug
product. This was because large-scale Phase 2 and 3 studies
demonstrating safety and efficacy had not been conducted
with LSD, which meant there were no data to submit in an
NDAor a sponsor to submit it.
Then, in July 1975, NIMH abruptly announced that it was
terminating all extramural (academic/medical center) funding
of clinical studies with LSD. The timing of this came just
weeks after the Washington Post and New York Times had
broken a major story: military and intelligence agencies had
been surreptitiously involved for 20 years in administering
LSD and other psychoactive drugs to military personnel and
civilians under the MKULTRA program, often by funding
academic researchers. FDA had even waived the requirement
for the military to conduct their drug studies under an IND
(Ruskin 1965), which freed researchers from having to obtain
informed consent, raising serious ethical issues. Thus, it is
likely that NIMH sought to rapidly distance itself from the
negative press by pulling out of the LSD clinical studies that
had failed to produce a marketed medication to treat psychiat-
ric illness. As the NIMH Research Task Force stated in 1975,
BAttempts to use [LSD]... as an adjunct to traditional psycho-
therapy or as a special type of psychotherapeutic intervention
have not clearly defined a therapeutic use^(Segal 1975).
Some 30 years later, NIMH (and NIDA) resumed funding
clinical research with hallucinogens such as psilocybin,
MDMA, and ketamine. In 2015, former NIMH Director
Tom Insel said, BNIMH is not opposed to work with psyche-
delics, but I doubt we would make a major investment^be-
cause Bit would be very difficult to get a pharmaceutical com-
pany interested in developing [them], since [they] cannot be
patented^(Pollan 2015). As reported in the federal website
ClinicalTrials.gov, most current studies with hallucinogens are
small-scale Phase 1 or Phase 2 pilot studies. These studies
may lay the foundation for future large-scale Phase 2 and 3
studies to demonstrate safety and efficacy of a drug for a
specific medical indication. As pilot investigations, these
modern human studies are similar to the those in the
1960sexcept that they fully comply with appropriate regu-
lations, ethics, and scientific standards for validity.
The history of human research with hallucinogens is still
unfolding, nearly a century after it began. This paper contrib-
utes a new dimension to other fine reviews of this history
(Campbell and Stark 2015; Carhart-Harris and Goodwin
2017; Doblin 2001;Grob1998; Hagenbach and
Werthmuller 2011; Lee and Shlain 1985; Mangini 1998;
Neill 1987; Novak 2004; Oram 2014,2016; Pollan 2015;
Walsh and Grob 2005; Yensen and Dryer 1992) by providing
specific regulatory reasons why LSD research diminished and
by systematically focusing on the degree to which researchers
conducting studies with LSD in the 1960s complied with (or
struggled with) FDA regulations that protect patients and
good science.
602 Psychopharmacology (2018) 235:591604
Acknowledgements The author gratefully acknowledges the valuable
discussion and comments regarding this paper provided by Dr. Silvia
Calderon (Controlled Substance Staff, FDA), Dr. John Swann (FDA
Historian), Ms. Nancy Sager (Office of Regulatory Policy, FDA), Dr.
Steven Grant (NIDA), Drs. Richard Yensen and Donna Dryer (Orenda
Institute), Dr. William Richards (Johns Hopkins University), Dr. Laura
Helft (Howard Hughes Medical Institute), and Mr. Jules Asher (NIMH
Press Office).
Compliance with ethical standards
Disclaimer This paper reflects the views of the author and does not
necessarily represent those of FDA.
References
Abramson HA (1967) Comparison of LSD with methysergide and psilo-
cybin on test subjects. In: Abramson HA (ed) The use of LSD in
psychotherapy and alcoholism. Bobbs-Merrill Company, Inc.,
Indianapolis
Asher J (1975) Whatever happened to psychedelic research? APA
Monitor on Psychology 6(10):45
Axelrod J. (2003) National Institutes of Health interview conducted by
Nirenberg M and Witkop B, November 25. https://history.nih.gov/
archives/downloads/Axelrod%20Julius.pdf
Barrigar RH (1964) Regulation of psychedelic drugs. Psychedelic Rev
1(4):394441
Beringer K (1927) Der Meskalinrausch: Seine Geschichte und
Erscheinungsweise (Monographien aus dem Gesamtgebiete der
Neurologie und Psychiatrie). Springer, Berlin
Buckman J (1966) Lysergic acid diethylamide. Brit Med J 2:302
Busch AK, Johnson WC (1950) LSD 25 as an aid in psychotherapy;
preliminary report of a new drug. Dis Nerv Syst 11(8):241243
Campbell ND, Stark L (2015) Making up vulnerablepeople: human
subjects and the subjective experience of medical experiment. Soc
Hist Med 28(4):825848
Carhart-Harris RL, Goodwin GM (2017) The therapeutic potential of psy-
chedelic drugs: past, present, and future. Neuropsychopharmacology
42(11):21052113
Carpenter D (2011) Reputation and power: organizational image and
pharmaceutical regulation at the FDA. Princeton University Press,
Princeton
Cole and Katz (1964) The psychotomimetic drugs: an overview. JAMA
187(10):758765
DAguanno W to Kelsey F, memo, September 19, (1963) Folder 505.51
September, Box 3570. General Subject Files 1938-1974, Division of
General Services, RG 88. FDA Records, National Archives II
(College Park, College Park, MD)
Debold RC, Leaf RC (eds) (1967) LSD, man and society. Wesleyan
University Press, Middletown
Dishotsky NI, Loughman WD, Mogar RE, Lipscomb WR (1971) LSD
and genetic damage. Science 172(3982):431440
Doblin R. Regulation of the medical use of psychedelics and mari-
juana. Harvard University dissertation, 2001. http://www.maps.
org/news/332-maps-resources/research-papers/5402-
dissertation-rick-doblin,-ph-d
Eisner BG (2002) Remembrances of LSD therapy past. www.maps.org/
images/pdf/books/remembrances.pdf
Faillace LA (1966) Clinical use of psychotomimetic drugs. Compr
Psychiatry 7(1):1320
FDA aide links LSD, birth defects (1968) Morning News, Wilmington,
Delaware
Food and Drug Administration (2001) Guidance for Industry: E10
Choice of Control Group and Related Issues in Clinical Trials
Food and Drug Administration (2017) Regulations, guidance, and reports
relatedtowomens health
Fortner v. Koch (1935) 272 Mich. 273, 261 N.W. 762
Freedman DX (1970) Problems and prospects of research with the hallu-
cinogens. In: Gamage JR, Zerkin EL (eds) Hallucinogenic drug
research: impact on science and society. Stash Press, Beloit
Goble FG (1970) The third force: the psychology of Abraham Maslow.
Pocket Books, New York
Goddard JL (1966) Organization and coordination of Federal Drug
Research and regulatory programs: LSD: hearings before the
United States Senate Committee on Government Operations,
Subcommittee on Executive Reorganization, Eighty-Ninth
Congress, Second Session
Green JA, Podolsky SH (2012) Reform, regulation, and pharmaceu-
ticals: the Kefauver-Harris amendments at 50. N Engl J Med
367:14811483
Grob CS (1998) Psychiatric research with hallucinogens: what have we
learned? Heffter Rev Psychedelic Res 1:820
Hagenbach D, Werthmuller L (2011) Mystic chemist: the life of Albert
Hofmann and his discovery of LSD. Synergetic Press, Santa Fe
Harvey JL to Stollaroff, letter. 1965 Box 3750, General Subject Files
1938-1974, Division of General Services, RG 88. FDA Records,
National Archives II (College Park, College Park, MD)
H.E.W (1975) Reported to Have Run LSD Tests on 2,500 People, New
York Times, New York, NY
Hilts PJ (2003) Protecting Americas health: the FDA, business, and one
hundred years of regulation. Alfred A. Knopf, New York
Hoffer A (1970) Treatment of psychosis with LSD. In: Gamage JR,
Zerkin EL (eds) Hallucinogenic drug research: impact on science
and society. Stash Press, Beloit
Hofmann A (1983) LSD, my problem child: reflections on sacred drugs,
mysticism, and science. J.P. Tarcher, Los Angeles
Hollister LE (1968) Chemical psychoses: LSD and related drugs. Charles
C. Thomas, Springfield, IL
Junod SW (2008) FDA and clinical drug trials: a short history. In: Davies
M, Kerimani F (eds) A quick guide to clinical trials. Bioplan Inc.,
Was h ingt o n
Kelsey FO (2014) Autobiographical reflections. https://www.fda.gov/
downloads/AboutFDA/WhatWeDo/History/OralHistories/
SelectedOralHistoryTranscripts/UCM406132.pdf
Kelsey FO (1966) Organization and coordination of Federal Drug
Research and regulatory programs: LSD: hearings before the
United States Senate Committee on Government Operations,
Subcommittee on Executive Reorganization, Eighty-Ninth
Congress, Second Session
Kelsey F et al. (1965) (FDA) meeting with Henze C and Bircher R
(Sandoz), memo. Folder 521.6-525.091. Box 3758, General Subject
Files 1938-1974, Division of General Services, RG 88. FDA Records,
National Archives II (College Park, College Park, MD)
Kurland AA, Unger S (1967) The psychedelic procedure in the treatment
of the alcoholic patient. In: Abramson HA (ed) The use of LSD in
psychotherapy and alcoholism. Bobbs-Merrill Company Inc.,
Indianapolis
Kurland AA, Unger S, Shaffer JW, Savage C (1967) Psychedelic therapy
utilizing LSD in the treatment of the alcoholic patient: a preliminary
report. Am J Psychiatry 123(10):12021209
Kurland A, Savage C, Pahnke WN, Grof S, Olsson JE (1971) LSD in the
treatment of alcoholics. Pharmakopsychiat 4:8394
Kurland AA (1997) American College on Neuropsychopharmacology
(ACNP) interview by Leo E. Hollister https://www.acnp.org/
programs/history.aspx#
Lee MA, Shlain B (1985) Acid dreams: the complete social history of
LSD: the CIA, the sixties, and beyond. Grove Press, New York
Psychopharmacology (2018) 235:591604 603
Lehmann HE (1993) Before they called it psychopharmacology.
Neuropsychopharmacology 8(4):291303
Long SY (1972) Does LSD induce chromosomal damage and
malformations? A review of the literature. Teratology 6(1):7590
Mangini M (1998) Treatment of alcoholism using psychedelic drugs: a
review of the program of research. J Psychoactive Drugs 30(4):381
418
Murphy RC (1967) A psychotherapists debt to LSD. In: Abramson HA
(ed) The use of LSD in psychotherapy and alcoholism. Bobbs-
Merrill Company, Inc., Indianapolis
Neill JR (1987) BMore than medical significance^:LSDandAmerican
psychiatry 1953 to 1966. J Psychoactive Drugs. (1):3945
NIH Almanac (2016) Chronology of Events. https://www.nih.gov/about-
nih/what-we-do/nih-almanac/chronology-events
Novak SJ (2004) LSD before Leary: Sidney Cohens critique of 1950s
psychedelic drug research. In: Tracy SW, Acker CJ (eds) Altering
American consciousness: the history of alcohol and drug use in the
United States, 18002000. University of Massachusetts Press,
Amherst
Oakley R, Ksir C (1999) Drugs, society, and human behavior. McGraw-
Hill Companies, Inc., New York
Oram M (2014) Efficacy and enlightenment: LSD psychotherapy and the
Drug Amendments of 1962. J Hist Med Allied Sci 69(2):221250
Oram M (2016) Prohibited or regulated? LSD psychotherapy and the
United States Food and Drug Administration. Hist Psychiatry
27(3):290306
Pohlman AD (1957) The use of d-amphetamine sulfate as an adjunct to
psychotherapy. J Clin Exp Psychopathol 18(2):159165
Pollan M (2015) The trip treatment. New Yorker
Richards W (2015) Sacred knowledge: psychedelics and religious expe-
riences. Columbia University Press, New York
Rinkel M, DeShon HJ, Hyde RW, Solomon HC (1952) Experimental
schizophrenia-like symptoms. Amer. J Psychiatry 108:572
Roseman v (1966) United States, 364 F. 2d 18Court of Appeals, 9th
circuit
Ruskin A meeting with Sim, VM, memo (1965) Folder 521.6-525.091.
Box 3758, General Subject Files 1938-1974, Division of General
Services, RG 88. FDA Records, National Archives II (College Park,
College Park, MD)
Savage C, Fadiman J, Mogar R, Allen MH (1967) Process and outcome
variables in psychedelic (LSD) therapy. In: Abramson HA (ed) The
use of LSD in psychotherapy and alcoholism. Bobbs-Merrill
Company Inc., Indianapolis
Segal J (ed) (1975) Research in the service of mental health: report of the
Research Task Force of the National Institute of Mental Health.
DHEW Publication Number (ADM) 75-236, Rockville
Schorr I memoto FDA. (1964) Folder 521.6-525.091. Box 3758, General
Subject Files 1938-1974, Divisionof General Services, RG 88. FDA
Records, National Archives II (College Park, College Park, MD)
Schumach M (1966) Distributor of LSD recalls all supplies. New York
Times. April 1966
Scully T (2013) Video: Ba sketch of the early history of LSD
manufacturing^.https://vimeo.com/75282865
Shorter E (2011) A brief history of placebos and clinical trials in psychi-
atry. Can J Psychiatr 56(4):193197
Stoll W (1947) Lysergsäure-diäthyl-amid, ein Phantastikum aus der
Mutterkorngruppe. Schweiz Arch Neur 60:12
Temple R (2011) Design of clinical trials. Presentation to FDAs clinical
investigator course, https://www.fda.gov/downloads/Training/
ClinicalInvestigatorTrainingCourse/UCM283377.pdf
Tjio JH, Pahnke WN, Kurland AA (1969a) LSD and chromosomes: a
controlled experiment. JAMA 210(5):849856
Tjio JH, Pahnke WN, Kurland AA (1969b) Pre- and post-LSD chromo-
somal aberrations: a comparative study. Adv Biochem
Psychopharmacol 1:191204
Tone A (2009) The age of anxiety: a history of Americas turbulent affair
with tranquilizers. Basic Books, New York
Unger SM (1964) LSDand psychotherapy: a bibliography of the English-
language literature. Psychedelic Review 1(4):44249
Unger S (1969) The psychedelic use of LSD: reflections and observa-
tions. In: Hicks RE, Fink PJ (eds) Psychedelic drugs. Grune and
Stratton, New York
US bars distribution of LSD ingredients (1966) New York Times
US makes LSD more available for research (1968) Medical World News
9(5):36
Walsh R, Grob CS (2005) Higher wisdom: eminent elders explore the
continuing impact of psychedelics. State University of New York
Press, Albany
Weinberger v. Hynson (1973) Wescott & Dunning, Inc 412 US. 609
Yensen R and Dryer D (1992) Thirty years of psychedelic research: the
Spring Grove experiments and its sequels. https://
associacaopsicodelica.files.wordpress.com/2015/09/30-anos-de-
pesquisa-com-psicodc3a9licos-yensen.pdf
Yolles SF (1966) Organization and coordination of Federal Drug
Research and regulatory programs: LSD: hearings before the
United States Senate Committee on Government Operations,
Subcommittee on Executive Reorganization, Eighty-Ninth
Congress, Second Session
604 Psychopharmacology (2018) 235:591604
... Many of the most prominent users and promotors of psychedelic substances have espoused social and political views contrary to those of political leaders in the US, which increased efforts to restrict access to these substances as part of the 1960's and 70's "War on Drugs." These efforts culminated in controlling psychedelic substances of abuse, and because they did not have accepted medical use they were placed in the highly restricted Schedule I of the 1970 US Controlled Substances Act (CSA) (Belouin and Henningfield, 2018;Bonson, 2018). The CSA criminalized the handling, possession, and distribution of hallucinogens except for highly constrained US Drug Enforcement Administration (DEA) registered research. ...
... The CSA criminalized the handling, possession, and distribution of hallucinogens except for highly constrained US Drug Enforcement Administration (DEA) registered research. In turn, US efforts contributed to generally similar global regulation by their inclusion in the United Nations (UN) Convention on Psychotropic Substances of 1971 (Spillane and McAllister, 2003; United Nations Office on Drugs and Crime, 2013; Bonson, 2018;Lampe, 2021;US Drug Enforcement Administration, 2022c;US Drug Enforcement Administration, 2022a). Schedule I control effectively and drastically reduced uncontrolled access to psychedelic substances by researchers and clinicians (Nutt et al., 2013;Belouin and Henningfield, 2018), however, US survey global monitoring showed that psychedelics and many other Schedule I substances, including cannabinoids, continued to be readily available and used for recreational and other purposes (Aikins, 2015;International Narcotics Control Board, 2021a;International Narcotics Control Board, 2021b;Substance Abuse and Mental Health Services Administration, 2021;Johnston et al., 2022). ...
... An ongoing point of discussion with FDA and among pharmaceutical developers is how many and what kinds of abuse-related studies will need to be conducted to support the approval of psychedelic medicines. Abuse potential research on psychedelic substances was conducted in the 1960s and 70s, however, methodological limitations noted in Bonson's overview of LSD regulation are important to keep in mind and bear careful consideration by today's researchers, because many of these studies are at best considered pilot or exploratory and not adequate to guide regulatory decision making (Belouin and Henningfield, 2018;Bonson, 2018;Calderon et al., 2018). At that time, all hallucinogens with abuse potential were placed in Schedule I since they were determined to have no accepted medical use in the US, whereas opioids, stimulants, sedatives, and other substances with abuse potential but which were recognized to have medical use were placed in Schedules II, III, IV, or V commensurate with their recognized level of abuse potential. ...
Article
New medicines containing classic hallucinogenic and entactogenic psychedelic substance are under development for various psychiatric and neurological disorders. Many of these, including psilocybin, lysergic acid diethylamide (LSD), and 3,4-methylenedioxymethamphetamine (MDMA) are Schedule I controlled substances of the United States Controlled Substances Act (US CSA), and similarly controlled globally. The implications of the CSA for research and medicines development, the path to approval of medicines, and their subsequent removal from Schedule I in the US are discussed. This entire process occurs within the framework of the CSA in the US and its counterparts internationally in accordance with international drug control treaties. Abuse potential related research in the US informs the eight factors of the CSA which provide the basis for rescheduling actions that must occur upon approval of a drug that contains a Schedule I substance. Abuse-related research also informs drug product labeling and the risk evaluation and mitigation strategies (REMS) will likely be required for approved medicines. Human abuse potential studies typically employed in CNS drug development may be problematic for substances with strong hallucinogenic effects such as psilocybin, and alternative strategies are discussed. Implications for research, medicinal development, and controlled substance scheduling are presented in the context of the US CSA and FDA requirements with implications for global regulation. We also discuss how abuse-related research can contribute to understanding mechanisms of action and therapeutic effects as well as the totality of the effects of the drugs on the brain, behavior, mood, and the constructs of spirituality and consciousness.
... classic psychedelic) lysergic acid diethylamide (LSD) in 1943 sparked notable scientific interest, with thousands of manuscripts, dozens of books, and a number of international conferences focused on LSDassisted psychotherapy (Grinspoon and Bakalar, 1979;Masters, 1973;Nutt et al., 2013;Passie et al., 2008). Due to a lack of modern methodological rigor, most of the early clinical studies of LSD are best understood as inconclusive, yielding only pilot data suggesting safety and efficacy (Bonson, 2018). Nevertheless, among the most promising findings was LSD's potential to treat alcohol dependence (Krebs and Johansen, 2012) and other substance use disorders (Savage and McCabe, 1973), as well as endof-life distress (Gasser et al., 2014). ...
Article
Background Classic psychedelics show promise in the treatment of mental health conditions; however, more scalable intervention protocols are needed to maximize access to these novel therapeutics. In this proof-of-concept study, perceptions of safety, subjective effects, and beliefs about the clinical utility of lysergic acid diethylamide (LSD) were evaluated among healthy participants ( N = 31) administered 50 to 100 µg LSD in a treatment paradigm conceptualized as more scalable than traditional approaches to administering classic psychedelics. Methods Semi-structured interviews assessed participants’ expectations, experience, and thoughts on the safety and efficacy of the study design. These interviews were transcribed for thematic analysis relating to perceptions of safety, subjective effects, and beliefs about the clinical utility of LSD. Results Most participants felt safe throughout the study, with a minority reporting concerns related to having a challenging experience that diminished over time. Participants attributed their feelings of safety to the study structure and support of their attendants, which allowed them to “let go” and immerse themselves in the experience without pre-occupation. Furthermore, participants reported transcendent, mystical-type experiences characteristic of classic psychedelics, with almost half highlighting the prominent role played by music during the acute period of drug action. Finally, participants endorsed support for the clinical utility of LSD in controlled environments, expressing the belief that LSD is safe and has the potential to help others. Conclusion Findings provide preliminary support for the feasibility of this scalable interventional paradigm and set the stage for future critical research with clinical populations.
... For example, prior to the scheduling and restrictions on the use of LSD, the NIH funded over 130 research projects on its prospective therapeutic benefits (Nutt et al., 2020). Unfortunately, the rigor of those studies was not up to current standards, and most were not adequately controlled (Bonson, 2018). However, these historical trials gave reason to suspect efficacy in the treatment of MDD and SUD. ...
Article
The studies of psychedelics, especially psychedelic tryptamines like psilocybin, are rapidly gaining interest in neuroscience research. Much of this interest stems from recent clinical studies demonstrating that they have a unique ability to improve the debilitating symptoms of major depressive disorder (MDD) long‐term after only a single treatment. Indeed, the Food and Drug Administration (FDA) has recently designated two Phase III clinical trials studying the ability of psilocybin to treat forms of MDD with "Breakthrough Therapy" status. If successful, the use of psychedelics to treat psychiatric diseases like depression would be revolutionary. As more evidence appears in the scientific literature to support their use in psychiatry to treat MDD on and substance use disorders (SUD), recent studies with rodents revealed that their therapeutic effects might extend beyond treating MDD and SUD. For example, psychedelics may have efficacy in the treatment and prevention of brain injury and neurodegenerative diseases such as Alzheimer Disease. Preclinical work has highlighted psychedelics' ability to induce neuroplasticity and synaptogenesis, and neural progenitor cell proliferation. Psychedelics may also act as immunomodulators by reducing levels of proinflammatory biomarkers, including IL‐1β, IL‐6, Tumor Necrosis Factor‐α (TNF‐α). Their exact molecular mechanisms, and induction of cellular interactions, especially between neural and glial cells, leading to therapeutic efficacy, remain to be determined. In this review, we discuss recent findings and information on how psychedelics may act therapeutically on cells within the Central Nervous System (CNS) during brain injuries and neurodegenerative diseases.
... 9 As psychedelics began to cross over into popular culture, a growing public sentiment against their widespread recreational use and their association with the 'counterculture movement' created a difficult environment for psychedelic researchers, particularly when Sandoz withdrew their sponsorship of LSD research in 1966 10 and transferred the rest of their supply to the National Institutes of Mental Health (NIMH). 11 Additionally, the implementation of the Kefauver-Harris Drug Amendments of 1962 to the Federal FD&C Act required researchers to formally prove the efficacy of pharmacological substances prior to use, which has been suggested to have particularly disrupted the progress of LSD psychotherapy as it did not account for the therapeutic method employed in these studies. 8 10 By the time the Controlled Substances Act of 1970 was passed, over one thousand scientific articles, which included over 40 000 individuals, had been published on psychedelic medicine, and several international conferences had been held. ...
Article
There is a growing resurgence in the study of psychedelic medicines for the treatment of mental health and substance use disorders. However, certain early investigations are marred by questionable research methods, abuses against research participants, and covert Central Intelligence Agency financial involvement. The purpose of this study was to understand how and to what extent people of colour and other vulnerable populations, specifically, individuals who were incarcerated or incapacitated due to mental health issues (inpatients with psychotic disorders), were exploited during the first wave of psychedelic research in the USA (1950–1980). To do so, we reviewed available empirical publications according to current ethical standards. Variables of interest included race and ethnicity of participants, population vulnerability, drug administration conditions, informed consent and undue influence. Our findings draw attention to the history of research abuses against people of colour in Western psychedelic research. In light of these findings, we urge a call-to-action to current psychedelic researchers to prioritise culturally inclusive and socially responsible research methods in current and future studies.
Chapter
This manuscript reviews research suggesting that classic psychedelics (5-HT2A receptor agonists) are effective in treating addictions including tobacco use disorder. I review historical research from the 1950s to 1970s suggesting that classic psychedelics are associated with addiction recovery across pharmacologically distinct drugs of addiction. I then review anthropological reports about ceremonial use of classic psychedelics and epidemiological studies that are consistent with anti-addiction efficacy. I review modern research using psilocybin in the treatment of alcohol use disorder and tobacco use disorder. Both lines of research show high success rates in preliminary studies. General anti-addiction efficacy across a variety of classes of addictive drugs is consistent with the notion that the persisting positive behavior change prompted by psychedelic therapy is due to amplification of psychotherapeutic processes. Future research should examine classic psychedelic treatment of additional substance use disorders including for opioids, cocaine, methamphetamine, and cannabis, and other disorders broadly characterized as addictions (e.g., obesity, problem gambling, hypersexual disorder). Future research should also explore addiction treatments with other classic psychedelics including LSD, mescaline, DMT, 5-MeO-DMT, and yet-to-be-discovered compounds. Experimental research is also needed to test different protocols for the delivery of classic psychedelic therapy for addictions. Given the staggering society costs of substance use disorders, including the mortality caused by tobacco smoking, it is critical that public funding be made available for scientists to follow up on promising early findings of classic psychedelics in addiction treatment. The costs and risks of not conducting such research are too great.
Article
Psychedelic substances have played important roles in diverse cultures, and ingesting various plant preparations to evoke altered states of consciousness has been described throughout recorded history. Accounts of the subjective effects of psychedelics typically focus on spiritual and mystical-type experiences, including feelings of unity, sacredness, and transcendence. Over the past 2 decades, there has been increasing interest in psychedelics as treatments for various medical disorders, including chronic pain. Although concerns about adverse medical and psychological effects contributed to their controlled status, contemporary knowledge of psychedelics suggests that risks are relatively rare when patients are carefully screened, prepared, and supervised. Clinical trial results have provided support for the effectiveness of psychedelics in different psychiatric conditions. However, there are only a small number of generally uncontrolled studies of psychedelics in patients with chronic pain (eg, cancer pain, phantom limb pain, migraine, and cluster headache). Challenges in evaluating psychedelics as treatments for chronic pain include identifying neurobiologic and psychosocial mechanisms of action and determining which pain conditions to investigate. Truly informative proof-of-concept and confirmatory randomized clinical trials will require careful selection of control groups, efforts to minimize bias from unblinding, and attention to the roles of patient mental set and treatment setting. Perspective There is considerable promise for the use of psychedelic therapy for pain, but evidence-based recommendations for the design of future studies are needed to ensure that the results of this research are truly informative.
Article
Background Advocates of the therapeutic use of psychedelic drugs have argued that a promising approach to treatment was prematurely abandoned in the 1960s primarily because of Richard Nixon's ‘War on Drugs’. This paper (1) briefly describes research in the 1950s and 1960s in North America on the use of LSD to treat alcohol dependence, anxiety in terminal illness, and anxiety and depression; and (2) discusses the factors that led to its abandonment. Method An analysis of historical scholarship on psychedelic research in the 1950s, 1960s and 1970s in North America. Results Research on psychedelic drugs in psychiatry was abandoned for a number of reasons that acted in concert. A major factor was that clinical research on psychedelic drugs was caught up in the tighter regulation of pharmaceutical research after the Thalidomide disaster in 1963. Psychedelic drugs also presented special challenges for randomised, placebo-controlled clinical trials in the 1970s that were not as positive as the claims made by their advocates in the 1950s and 1960s. Clinical research became more difficult after 1965 when Sandoz ceased providing psychedelic drugs for research and their nonmedical use was prohibited in 1970. Conclusions The demise of psychedelic drug research was not solely due to the ‘War on Drugs’. It was hastened by tighter regulation of pharmaceutical research, the failure of controlled clinical trials to live up to the claims of psychedelic advocates, and the pharmaceutical industry's lack of interest in funding clinical trials.
Article
Background Classical psychedelics are a group of drugs which act as agonists on the serotonin-2A (5-HT2A) receptor. Evidence suggests they may have a uniquely rapid and enduring positive effect on mood. However, marked heterogeneity between methodological designs in this emerging field remains a significant concern. Aims To determine how differences in the type of psychedelic agent used and the number of dosing sessions administered affect subjects’ depression and anxiety outcomes and adverse drug reactions (ADR). Methods This review collected and screened 1591 records from the MEDLINE and Web of Science databases for clinical trials reporting objective data on mood for subjects with a known anxiety or depression. Results After screening, nine clinical trials met inclusion criteria. Meta-analysis of these studies showed significant, large positive effect sizes for measures of anxiety (Cohen’s d = 1.26) and depression (Cohen’s d = 1.38) overall. These positive effects were also significant at acute (⩽1 week) and extended (>1 week) time points. No significant differences were observed between trials using different psychedelic agents (psilocybin, ayahuasca or lysergic acid diethylamide (LSD)), however, a significant difference was observed in favour of trials with multiple dosing sessions. No serious ADR were reported. Conclusion Psilocybin, ayahuasca and LSD all appear to be effective and relatively safe agents capable of producing rapid and sustained improvements in anxiety and depression. Moreover, the findings of the present analysis suggest that they may show a greater efficacy when given to patients over multiple sessions as compared to the more common single session used in many of the existing trials.
Article
Full-text available
Plant-based psychedelics such as psilocybin have an ancient history of medicinal use. After the first English-language report on LSD in 1950, psychedelics enjoyed a short-lived relationship with psychology and psychiatry. Used most notably as aides to psychotherapy for the treatment of mood disorders and alcohol dependence, drugs such as LSD showed initial therapeutic promise before prohibitive legislature in the mid-1960s effectively ended all major psychedelic research programmes. Since the early 1990s, there has been a steady revival of human psychedelic research: last year saw reports on the first modern brain imaging study with LSD and 3 separate clinical trials of psilocybin for depressive symptoms. In this Circumspective piece, Robin Carhart-Harris and Guy Goodwin share their opinions on the promises and pitfalls of renewed psychedelic research, with a focus on the development of psilocybin as a treatment for depression.Neuropsychopharmacology accepted article preview online, 26 April 2017. doi:10.1038/npp.2017.84.
Conference Paper
Full-text available
In the late 1960's a multi-million dollar interdisciplinary research center opened in the State of Maryland. This center for psychiatric research was a consequence of research in psychedelic psychotherapy performed by Albert Kurland and his associates at the Spring Grove State Hospital. Though the studies at Spring Grove State Hospital and those that followed at the Maryland Psychiatric Research Center (MPRC) ended in 1976, they remain the largest, most sustained and systematic study of psychedelic drugs and psychotherapy yet attempted.
Article
Over the 1950s and early 1960s, the use of the hallucinogenic drug lysergic acid diethylamide (LSD) to facilitate psychotherapy was a promising field of psychiatric research in the USA. However, during the 1960s, research began to decline, before coming to a complete halt in the mid-1970s. This has commonly been explained through the increase in prohibitive federal regulations during the 1960s that aimed to curb the growing recreational use of the drug. However, closely examining the Food and Drug Administration’s regulation of LSD research in the 1960s will reveal that not only was LSD research never prohibited, but that the administration supported research to a greater degree than has been recognized. Instead, the decline in research reflected more complex changes in the regulation of pharmaceutical research and development.
Chapter
Although the cause of psychosis may be unknown, there is a generally effective acute treatment for this idiopathic condition. Typically it involves administration of antipsychotic drugs, all of which have in common the characteristic of post-synaptic dopamine blockade. Upon administration of the appropriate dosage of such a drug, hallucinations disappear, delusional activity subsides, thought disorder abates, and affective disturbance becomes normal. This much is generally beyond dispute. The focus of the current debate on these clinical issues concerns the optimal strategy of drug dosage and duration and the methods by which these can be determined.