Human Hallucinogen Research: Guidelines for Safety

Abstract

There has recently been a renewal of human research with classical hallucinogens (psychedelics). This paper first briefly discusses the unique history of human hallucinogen research, and then reviews the risks of hallucinogen administration and safeguards for minimizing these risks. Although hallucinogens are relatively safe physiologically and are not considered drugs of dependence, their administration involves unique psychological risks. The most likely risk is overwhelming distress during drug action ('bad trip'), which could lead to potentially dangerous behaviour such as leaving the study site. Less common are prolonged psychoses triggered by hallucinogens. Safeguards against these risks include the exclusion of volunteers with personal or family history of psychotic disorders or other severe psychiatric disorders, establishing trust and rapport between session monitors and volunteer before the session, careful volunteer preparation, a safe physical session environment and interpersonal support from at least two study monitors during the session. Investigators should probe for the relatively rare hallucinogen persisting perception disorder in follow-up contact. Persisting adverse reactions are rare when research is conducted along these guidelines. Incautious research may jeopardize participant safety and future research. However, carefully conducted research may inform the treatment of psychiatric disorders, and may lead to advances in basic science.

Full text

Human hallucinogen research:
guidelines for safety
MW Johnson Department of Psychiatry and Behavioral Sciences, Johns Hopkins University, School of Medicine,
Baltimore, MD, USA.
WA Richards Johns Hopkins Bayview Medical Center, Baltimore, MD, USA.
RR Griffiths Department of Psychiatry and Behavioral Sciences, Johns Hopkins University, School of Medicine,
Baltimore, MD, USA; Department of Neuroscience, Johns Hopkins University, School of Medicine, Baltimore, MD, USA.
Abstract
There has recently been a renewal of human research with classical
hallucinogens (psychedelics). This paper first briefly discusses the unique
history of human hallucinogen research, and then reviews the risks of
hallucinogen administration and safeguards for minimizing these risks.
Although hallucinogens are relatively safe physiologically and are not
considered drugs of dependence, their administration involves unique
psychological risks. The most likely risk is overwhelming distress during
drug action (‘bad trip’), which could lead to potentially dangerous
behaviour such as leaving the study site. Less common are prolonged
psychoses triggered by hallucinogens. Safeguards against these risks
include the exclusion of volunteers with personal or family history of
psychotic disorders or other severe psychiatric disorders, establishing trust
and rapport between session monitors and volunteer before the session,
careful volunteer preparation, a safe physical session environment and
interpersonal support from at least two study monitors during the session.
Investigators should probe for the relatively rare hallucinogen persisting
perception disorder in follow-up contact. Persisting adverse reactions are
rare when research is conducted along these guidelines. Incautious
research may jeopardize participant safety and future research. However,
carefully conducted research may inform the treatment of psychiatric
disorders, and may lead to advances in basic science.
Key words
5-HT
2A
agonists; adverse reactions; DMT; entheogens; hallucinogens;
human research; LSD; mescaline; psilocybin; psychedelics; safety
guidelines
Introduction
After several decades of dormancy, research involving the
administration of classical hallucinogens to humans has been
recently renewed (Sessa, 2005; Frecska and Luna, 2006; Har-
vard Mental Health Letter, 2006; Lancet, 2006; Morris, 2006;
Winkelman and Roberts, 2007). Although nonhuman animal
research during the intervening decades has substantially
advanced our understanding of underlying neuropharmacolog-
ical mechanisms of the hallucinogens, the fact that human
research with this historically important and widely used class
of compounds remained inactive is remarkable (Nichols, 2004).
Renewed human administration research began with the work of
Rick Strassman, who initiated research on the effects of
N,N-dimethyltryptamine (DMT) at the University of New
Mexico in the early 1990s (Strassman, 1991, 1996, 2001;
Strassman and Qualls, 1994; Strassman, et al., 1994, 1996). Sub-
sequently, investigators both in the USA and in Europe have
developed human research programmes with hallucinogens.
This new research has included basic science studies that have
administered hallucinogens as tools for investigating cognitive
neuroscience and perception (Gouzoulis-Mayfrank, et al., 1998a;
Gouzoulis-Mayfrank, et al., 2002; Umbricht, et al., 2003; Carter,
et al., 2004; Carter, et al., 2005a,b), time perception (Wittmann,
et al., 2007), hallucinogen pharmacokinetics and metabolism
(Hasler, et al., 1997, 2002), model psychosis (Vollenweider,
et al., 1997, 1998, 1999, 2007; Gouzoulis-Mayfrank, et al.,
1998a; Vollenweider and Geyer, 2001; Gouzoulis-Mayfrank,
et al., 2005, 2006), and, recently in our laboratory, hallucinogens’
reported facilitation of experiences having enduring personal
meaning and spiritual significance (Griffiths, et al., 2006). Recent
clinical studies have administered hallucinogens to evaluate their
safety and efficacy in the treatment of psychiatric disorders:
specifically, anxiety related to advanced-stage cancer (Grob,
2005) and obsessive-compulsive disorder (Moreno, et al., 2006).
In addition, several studies have examined the effects of
Original Papers
Journal of Psychopharmacology
22(6) (2008) 603–620
©2008 British Association
for Psychopharmacology
ISSN 0269-8811
SAGE Publications Ltd,
Los Angeles, London,
New Delhi and Singapore
10.1177/0269881108093587
Corresponding author: Roland Griffiths, Department of Psychiatry and Behavioral Sciences, Johns Hopkins University, School of Medicine, 5510 Nathan Shock Drive, Baltimore,
MD, USA. Email: rgriff@jhmi.edu
by Krystle Cole on October 29, 2008 http://jop.sagepub.comDownloaded from

ayahuasca (also known as hoasca or yagé;anadmixture
containing DMT) in human volunteers outside of the USA
(Grob, et al., 1996; Riba, et al., 2001). Because the United States
Supreme Court has recently ruled in favour of the União do
Vegetal (UDV; a syncretic Brazilian church that uses ayahuasca
in the context of religious ceremonies) in their claim that the
UDV’suseofayahuasca is protected under the Religious
Freedom Restoration Act (Gonzales v. O Centro Espirita Bene-
ficiente União do Vegetal, 2006), ayahuasca use within this
church setting may receive increased scientific investigation
within the USA.
We use the word ‘hallucinogen’herein to refer to the
classical hallucinogens, sometimes called ‘psychedelics’,
‘psychotomimetics’or ‘entheogens’(Grinspoon and Bakalar,
1979; Ruck, et al., 1979; Ott, 1996; Metzner, 2004). Admittedly,
the term ‘hallucinogen’is not ideal for these substances, because
perceptual changes are only one domain of their effects, and the
typical perceptual changes engendered by hallucinogens at typical
doses rarely include frank hallucinations (Grinspoon and
Bakalar, 1979; Nichols, 2004; O’Brien, 2006). However, we use
this term because it is the most widely used in the scientific litera-
ture. Although the term ‘psychedelic’is widely used, it has the
disadvantage of carrying considerable cultural connotation (i.e.
its use as a descriptor of a style of music or art associated with
Western counter-culture of the 1960s). The terms ‘psychotomi-
metic’(emphasizing model psychosis) and ‘entheogen’(empha-
sizing mystical-type experiences, i.e. phenomenologically indistin-
guishable from classically described mystical experiences)
highlight only a single aspect (which may not occur reliably) of
the much broader range of hallucinogen effects.
Hallucinogens can be divided structurally into two classes
of alkaloids: the tryptamines, including psilocybin (prodrug con-
stituent of Psilocybe and several other mushroom genera), the
semi-synthetic d-lysergic acid diethylamide (LSD), and DMT;
and the phenethylamines, including mescaline (principle active
constituent of peyote) and certain synthetic compounds
(Grinspoon and Bakalar, 1979; Shulgin and Shulgin, 1991,
1997; Metzner, 2004, Nichols, 2004). The effects of these
substances are primarily mediated by agonist action at 5-HT
2A
receptors (Glennon, et al., 1984; Nichols, 2004; González-
Maeso, et al., 2007) and produce a generally similar profile of
subjective effects (Hidalgo, 1960; Hollister and Hartman, 1962;
Wolbach, et al., 1962a,b; Shulgin and Shulgin, 1991, 1997).
Other classes of substances have sometimes been identified as
‘hallucinogens’, including 3,4-methylenedioxymethamphetamine
or MDMA [perhaps more appropriately labelled an entactogen
(Nichols, et al., 1986) or empathogen (Metzner, 1985)]; dissocia-
tive anaesthetics such as ketamine, phencyclidine and dextro-
methorphan; and anticholinergic agents such as scopolamine
and atropine (Nichols, 2004). However, this paper uses the term
‘hallucinogen’to refer specifically to classical hallucinogens.
The purpose of this paper is to provide guidance in the safe
administration of high doses of hallucinogens (e.g. ≥25 mg
psilocybin or 200 μg LSD). Some aspects of these recommenda-
tions may also apply to studies employing lower doses, although,
as with other drug classes, the likelihood of potential adverse
effects will be related to dose. Similarly, some aspects of these
recommendations may also apply to studies administering
the other drug classes mentioned in the preceding paragraph:
entactogens, dissociative anaesthetics and anticholinergic agents.
However, the clinical effects and mechanisms of action of these
agents are sufficiently different from the classical hallucinogens
that safety recommendations concerning their administration
are beyond the scope of this manuscript.
First, so that the historical context in which current human
hallucinogen studies are conducted will be clear, we will briefly
discuss the history of sacramental hallucinogen use by indigenous
cultures, and the history of human hallucinogen research before it
became dormant in the 1970s. The decades-long virtual dor-
mancy of human hallucinogen research stands as a unique case
in the history of modern clinical pharmacology. It is important
for researchers going forward to understand the role that safety
factors, as well as sociological and political factors, played in the
history and cessation of human hallucinogen research. Moreover,
because of the historical legacy of sensationalism surrounding
hallucinogens, researchers should appreciate the precarious posi-
tion of current human hallucinogen research, and recognize that
very high safety standards will help to ensure that human research
continues into the decades to come. Next, we will provide a
detailed description of the unique risks of hallucinogen adminis-
tration. We will then present the proposed guidelines for conduct-
ing high-dose hallucinogen research in each of several domains,
including volunteer selection, study personnel, physical environ-
ment, preparation of volunteers, conduct of sessions, and post-
session procedures.
Relevant history
Hallucinogen use by indigenous cultures
Hallucinogens have been used by indigenous cultures for millennia
(Schultes, 1969; Lowy, 1971; Schultes, et al., 2001). These cultures
have restricted hallucinogen use to sacramental and healing
contexts, with these two often being inseparably intertwined.
Remarkably, apparently without exception, such cultures view
hallucinogenic plants and fungi as being of divine origin (Schultes,
et al., 2001). Given this orientation, it is not surprising that their
ingestion is often tightly restricted, with use controlled by
ceremonial guidelines, including taboos against improper use
(Schultes, et al., 2001; Weil, 2004). Indigenous cultures restrict
use of hallucinogens to highly ritualized, sacred ceremonies such
as those designed to serve as rites of passage, or to set the occasion
for divination and spiritual or physical healing. Even in cases in
which certain use extends beyond the shaman and may be more
recreational in nature (e.g. use of the DMT-containing epená by
the Waiká cultures of Brazil and Venezuela), the hallucinogen is
prepared and taken in a highly ritualized context (Grinspoon and
Bakalar, 1979; Schultes, et al. 2001; Weil, 2004). Modern, urban
syncretic religions, such as the UDV, which have developed in
South America and have been influenced by indigenous use of
ayahuasca, also incorporate a high degree of structure and
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guidance into their ayahuasca use, which may minimize adverse
reactions (Gonzales v. O Centro Espirita Beneficiente União do
Vegetal, 2006).
However, indigenous cultures should not be regarded as
absolute role models in the clinical use of hallucinogens for at
least two reasons. First, some of these cultures also engaged in
practices considered unethical in our culture. For example, the
Aztecs, who used psilocybin mushrooms and morning glory
seeds (containing LSD-related agents), practiced human sacrifice,
and even incorporated hallucinogen use into sacrificial rituals
(Ott, 1996). As another example, the Jivaro in Ecuador who use
ayahuasca practice sacramental headhunting, and ayahuasca may
be used by the shaman in that society for malevolent intent (i.e.
bewitching) as well as for healing (Harner, 1962, 1968; Grof,
1977). Second, risk/benefit tradeoffs that may be acceptable in
various religious contexts may fall short of what is expected in
the domain of contemporary scientific research with human
participants.
Nonetheless, some important themes have emerged in the use
of hallucinogens by indigenous cultures that may have bearing on
the appropriate use of hallucinogens in clinical research. Indeed,
some of the safeguards developed for clinical hallucinogen
research and expressed in the guidelines presented herein are
similar to important aspects of hallucinogen use by indigenous
cultures. These common themes are structured use (expressed as
ritual in indigenous use), restrictions on use including the need for
guidance and appreciation of hallucinogens’powerful psycho-
logical effects (expressed as reverence in indigenous use). We
believe that these commonalities are more than coincidence. The
unique pharmacology of classical hallucinogens may have shaped
convergent practices across independent cultures. Likewise, the
guidelines expressed herein for human clinical research with
hallucinogens may also be viewed as having been developed in
reaction to these same aspects of hallucinogen pharmacology.
As an example, some of the unique effects and safety concerns
for hallucinogens may be related to their ability to set the
occasion for deeply meaningful, even spiritual experiences
(Richards, 2003, 2005). Novak (1997) hypothesized that Western
intellectuals in the mid 1950s such as Aldous Huxley and Gerald
Heard merely redefined the subjective effects resulting from
hallucinogen administration as a spiritual experience, thereby
popularizing such an association in western culture. However,
the observation that indigenous cultures that ingest classical
hallucinogens almost invariably do so under sacramental con-
texts (Schultes, et al., 2001), along with the findings from
double-blind clinical studies demonstrating that under supportive
conditions, hallucinogens occasion mystical-type experiences
with high frequency (Pahnke, 1963; Griffiths, et al., 2006) sug-
gests that the association of hallucinogens with spiritual experi-
ence relates to the pharmacology of these agents rather than
being based entirely on cultural suggestion.
Early clinical research
In the 1950s and 1960s, thousands of research participants were
administered hallucinogens in the context of basic clinical
research or therapeutic clinical research, resulting in hundreds
of publications (Grinspoon and Bakalar, 1979; Grob, et al.,
1998; Strassman, 2001; Nichols, 2004). During this time, the
United States Army investigated classical hallucinogens as
incapacitating agents in soldiers, and the United States Central
Intelligence Agency conducted clandestine research investiga-
ting classical hallucinogens as interrogation agents in which
civilians were administered hallucinogens without knowledge
or consent. Eventually, both groups ceased to focus on classical
hallucinogens in favour of non-classical ‘hallucinogens’such as
the synthetic anticholinergic compound quinuclidinyl benzilate
(BZ), which showed greater promise as a warfare agent than
LSD because its effects were marked by greater immobility,
delirium, amnesia and duration (Lee and Shlain, 1992). Very
early academic research on classical hallucinogens was
designed without considering the powerful influences of set
(psychological state) and setting (environment) (Malitz, et al.,
1960; Rinkel, et al., 1960; Hollister, 1961; Rümmele and
Gnirss, 1961; Leuner, 1962). Subsequent research, which
included more preparation and interpersonal support during
the period of drug action, found fewer adverse psychological
reactions, such as panic reactions and paranoid episodes, and
increased reports of positively valued experiences (Chwelos,
et al., 1959; Leary, 1964; Leary, et al., 1963, 1964; Metzner,
et al., 1965; Pahnke, 1969).
One major area of early research focused on the comparison
of hallucinogen effects with the symptoms of psychosis (e.g.
Stockings, 1940; Hoch, et al., 1953; Hoffer and Callbeck,
1960; Leuner, 1962; Kuramochi and Takahashi, 1964).
Although the study of hallucinogens as models for the
psychosis observed in schizophrenia eventually fell out of
favour in psychiatry (Grinspoon and Bakalar, 1979; Snyder,
1988; Strassman, 2001), a renewed interest in this area is
emerging, in part due to modern brain imaging techniques
and neuropharmacological findings that have supported
hallucinogens as a model of at least certain aspects of acute
psychosis (Vollenweider, et al., 1997; Gouzoulis-Mayfrank,
et al., 1998a; Vollenweider and Geyer, 2001; Gouzoulis-
Mayfrank, et al., 2005, 2006).
Other areas of early human research included investigations
of therapeutic applications of hallucinogens in treatment of
psychological suffering associated with cancer and in the treat-
ment of substance dependence. Anecdotal observations and
non-blind studies in cancer patients suffering from anxiety
and depression suggested that LSD administration resulted in
an ability to openly discuss existential fears and be at peace
with approaching death, and that this reorientation often out-
lasted the acute drug effects (Kast and Collins, 1964; Cohen,
1965; Kast, 1967). Follow-up investigations involved the
administration of a high dose of a hallucinogen to carefully
prepared patients under highly supportive interpersonal
conditions, with the patient wearing eyeshades and listening
to classical music through headphones during the course of
pharmacological action, a model known as ‘psychedelic peak
therapy’or ‘psychedelic therapy’(Kurland, et al., 1969;
Pahnke, et al., 1969; Richards, et al, 1972; Grof, et al., 1973;
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Kurland, et al., 1973; Grof and Halifax, 1977; Richards, et al.,
1977, 1979; Grof, 1980; Richards, 1980; Kurland, 1985).
Unfortunately, these early studies did not include the stringent
control conditions or groups that now have become standard in
modern clinical psychopharmacology research. The results sug-
gest, however, that these compounds may have improved
psychological well-being in the face of anxiety and depression
secondary to cancer.
Another focus of study was hallucinogen-facilitated therapy
in the treatment of alcoholism and other forms of substance
dependence (e.g. Smart, et al., 1966; Hollister, et al., 1969;
Ludwig, et al., 1969; Kurland, et al., 1971; Savage and
McCabe, 1973). While some studies prepared patients and
utilized supportive conditions (e.g. Kurland, et al., 1971;
Savage and McCabe, 1973), others drastically departed from
the ‘psychedelic therapy’model (and from the guidelines
herein), and involved the administration of high doses to
unprepared, restrained patients (e.g. Smart, et al., 1966).
Results across studies were ultimately inconclusive due to
such variations in methods and a lack of modern controls and
experimental rigour (Abuzzahab and Anderson, 1971;
McGlothlin and Arnold, 1971; Halpern, 1996; Mangini,
1998). Similarly, some therapists reported that hallucinogens
administered under supportive contexts could accelerate
psychotherapy for a variety of psychological disorders (e.g.
Abramson, 1960, 1963; Crochet, et al., 1963; Mogar and
Aldrich, 1969; Rhead, 1977). However, these reports were
largely based on anecdotal clinical accounts rather than con-
trolled studies.
Escalation in recreational hallucinogen use, primarily LSD,
in the 1960s, led to considerable sensationalism concerning
these drugs in media coverage. Adding to the controversy was
the publicized departure and termination of Timothy Leary
and Richard Alpert from Harvard University in 1963 following
charges of unorthodox methods in hallucinogen research
(Grinspoon and Bakalar, 1979; Lee and Shlain, 1992; Novak,
1997; Strassman, 2001). Leary’s subsequent irresponsible
advocacy of hallucinogen use by youth further undermined an
objective scientific approach to studying these compounds. The
growing controversy and sensationalism resulted in increasing
restrictions on access to hallucinogens throughout the 1960s
(ultimately resulting in the placement of the most popular
hallucinogens into Schedule I of the 1970 Controlled
Substances Act in the United States), creating substantially
greater regulatory barriers for researchers to conduct human
trials. The negative publicity also resulted in withdrawal of
federal research funds, which had previously supported much
of the human research, and in the professional marginalization
of clinical investigators interested in pursuing research with
hallucinogens. Human research with hallucinogens in the
USA became virtually dormant when the last trials were
published in the early 1970s. Commenting on the unusual
evolution of psychiatric research with hallucinogens, Strassman
(2001) mused, “They began as ‘wonder drugs,’turned into
‘horror drugs,’then became nothing”(p. 28).
Unique risks of human hallucinogen research
Hallucinogen administration in humans results in a unique
profile of effects and potential adverse reactions that need to
be appropriately addressed to maximize safety. Different risks
are associated with different drug classes, and human research
with each class requires procedures to be in place to address
those particular risks. For example, because high doses of
certain opioids and sedative/hypnotics can cause respiratory
depression (Gutstein and Akil, 2006; Charney, et al., 2006),
when conducting research with high doses of these drugs,
respiration rate and/or blood oxygen are monitored, and
mechanical breathing assistance and appropriate rescue
medications are readily available. As another example,
administration of high doses of psychomotor stimulants, such
as cocaine, can cause cardiac stress (O’Brien, 2006). Therefore,
electrocardiogram (ECG) readings taken at screening are
scrutinized carefully, pulse and blood pressure are monitored
during sessions, and rescue medication for acute hypertension
is immediately available. Similarly, human hallucinogen
administration entails its own unique risk profile. Unlike
opioids, sedative/hypnotics or psychomotor stimulants, the
primary safety concerns with hallucinogens are largely
psychological rather than physiological in nature.
Physiological toxicity
Hallucinogens generally possess relatively low physiological
toxicity, and have not been shown to result in organ damage
or neuropsychological deficits (Strassman, 1984; Gable, 1993,
2004; Halpern and Pope, 1999; Hasler, et al., 2004; Nichols,
2004; Halpern, et al., 2005). Nonhuman animal studies have
shown MDMA (structurally similar to some classical halluci-
nogens, but with a substantially different pharmacological
mechanism of action) to have neurotoxic effects at high doses,
although MDMA has been judged to be safe for human
administration in the context of several therapeutic and basic
human research studies. In contrast, there is no evidence of
such potential neurotoxic effects with the prototypical classical
hallucinogens (i.e. LSD, mescaline and psilocybin). Some
physiological symptoms may occur during hallucinogen action,
such as dizziness, weakness, tremors, nausea, drowsiness,
paraesthesia, blurred vision, dilated pupils and increased
tendon reflexes (Isbell, 1959; Hollister, 1961; Nichols, 2004).
In addition, hallucinogens can moderately increase pulse and
both systolic and diastolic blood pressure (Isbell, 1959;
Wolbach, et al., 1962b; Strassman and Qualls, 1994;
Gouzoulis-Mayfrank, et al., 1999; Passie, et al., 2000; Griffiths,
et al., 2006). However, these somatic effects vary and are
relatively unimpressive even at doses yielding powerful psycho-
logical effects (perceptual, cognitive and affective) (Metzner,
et al., 1965; Passie, et al., 2000; Metzner, 2004).
Although a full discussion of special physiological toxicity
concerns for medical patient populations is beyond the scope of
this manuscript, a few observations are worthy of note. The
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early literature examining hallucinogens in the treatment of
anxiety and depression secondary to cancer indicated that the
classical hallucinogens LSD and N,N-dipropyltryptamine
(DPT) were physiologically well-tolerated. The physical
adverse effects of these agents observed in cancer patients
were manageable and similar to effects observed in physically
healthy individuals. These researchers noted that any other
symptoms experienced during sessions with cancer patients
were symptoms already associated with their existing illness
(Richards, et al., 1972; Kurland, et al., 1973; Kurland, 1985).
Early clinical research also safely administered LSD to chronic
alcoholics and cancer patients with ‘considerable liver dam-
age’, suggesting hepatic concerns are ‘negligible unless the dys-
function is of a critical degree’(Grof, 1980, p. 164).
Participants and review committees may be concerned that
LSD or other hallucinogens are associated with chromosomal
damage. These concerns stem from an anti-LSD media
campaign by the USA government in the late 1960s that was
based on and followed soon after initial reports (Cohen, et al.,
1967a,b; Irwin and Egozcue, 1967), suggesting that LSD
caused chromosomal damage in human leucocytes (Ott, 1996;
Weil, 2004). This campaign included pictures of deformed
children (Grinspoon and Bakalar, 1979) at a time when the
thalidomide tragedies of a decade earlier were relatively fresh
in the public’s memory (Ott, 1996). However, many follow-up
investigations soon squarely refuted the hypothesis that LSD
use in humans was a significant risk for chromosomal damage
or carcinogenic, mutagenic or teratogenic effects (e.g. Bender
and Siva Sankar, 1968; Tjio, et al., 1969; Dishotsky, et al.,
1971; Long, 1972).
Abuse and dependence
Like many classes of psychoactive drugs, hallucinogens are
sometimes used in a manner that jeopardizes the safety or
well-being of the individual or others (e.g. driving while
impaired; a pattern of use that interferes with work, school or
relationships). Under such circumstances, hallucinogens are
said to be ‘abused’. However, hallucinogens are not typically
considered drugs of dependence in that they do not engender
compulsive drug seeking (National Institute on Drug Abuse,
2001, 2006; O’Brien, 2006), consistent with the observation
that they are not reliably self-administered in nonhuman
animals (Poling and Bryceland, 1979; Griffiths, et al., 1980;
Fantegrossi, et al., 2004). Furthermore, they are not associated
with a known withdrawal syndrome (O’Brien, 2006). There-
fore, there is little risk that exposing human volunteers to
hallucinogens will leave participants physically or psycho-
logically dependent on these compounds. This low dependence
potential allows for the possibility of administering these
compounds to hallucinogen-naïve volunteers when blinding
issues are critical (e.g. Griffiths, et al., 2006). However, in cer-
tain situations it may be advantageous to study hallucinogen-
experienced participants (e.g. brain imaging studies requiring
the participant to remain immobile).
Acute psychological distress and dangerous
behaviour during hallucinogen action
Although hallucinogens have relatively low physiological toxicity
and are not associated with compulsive drug seeking, there is still
concern that they may pose other psychological risks. The most
likely risk associated with hallucinogen administration is
commonly known as a ‘bad trip’and is characterized by anxiety,
fear/panic, dysphoria, and/or paranoia. Distressing effects may be
experienced in a variety of modalities: sensory (e.g. frightening
illusions), somatic (e.g. disturbing hyperawareness of physiologi-
cal processes), personal psychological (e.g. troubling thoughts or
feelings concerning one’s life) and metaphysical (e.g. troubling
thoughts or feelings about ultimate evil forces) (McCabe, 1977;
Grinspoon and Bakalar, 1979; Strassman, 1984). Because
emotional experience is often intensified when under the influence
of a hallucinogen, in unprepared individuals or uncontrolled
situations any of these effects may potentially escalate to danger-
ous behaviour. For example, fear and paranoid delusions may
lead to erratic and potentially dangerous behaviours, including
aggression against self or others (Strassman, 1984). Although
very rare, in hazardous and unsupervised conditions, individuals
under the influence of hallucinogens have ended their lives by
such acts as jumping from buildings (Keeler and Reifler, 1967;
Reynolds and Jindrich, 1985; Reitman and Vasilakis, 2004;
O’Brien, 2006). We recognize that even under unsupervised and
unprepared conditions, reactions to hallucinogens involving
violence and self-destructive behaviour are rare, and our intention
is not to create an unrealistic account of the dangers of hallucino-
gens. Nonetheless, even infrequent reports of such dangers
require that investigators take seriously such risks and take steps
to avoid their occurrence.
Prolonged psychosis
Another potential risk of hallucinogen administration is
provoking the onset of prolonged psychosis, lasting days or
even months (Strassman, 1984). Although determining causa-
tion is difficult, it appears that individuals who experience such
reactions have premorbid mental illness before taking halluci-
nogens. However, it is unknown whether the precipitation of
psychosis in such susceptible individuals represents a psychotic
reaction that would have never occurred in the absence of
hallucinogen use, or whether it represents an earlier onset of a
psychotic break that would have inevitably occurred
(Grinspoon and Bakalar, 1979; Strassman, 1984). Unlike
acute psychological distress, these cases will be extremely rare
in well-selected and well-prepared participants. In a survey of
investigators who had administered LSD or mescaline, Cohen
(1960) reported that only a single case of a psychotic reaction
lasting more than 48 h occurred in 1200 experimental (non-
patient) research participants (a rate of 0.8 per 1000). Notably,
the individual was an identical twin of a schizophrenic patient
and thus would have been excluded under the proposed guide-
lines. Prolonged reactions over 48 h were slightly more frequent
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in patients undergoing psychotherapy than in experimental
non-patient participants, but still relatively rare, occurring at
a rate of 1.8 prolonged reactions per 1000 patients. Cohen
(1960) also reported that suicide attempts and completed
suicides occurred at a rate of 1.2 and 0.4, respectively, per
1000 patients. The causal link between hallucinogen exposure
and suicide or suicide attempt was only clear for a portion of
these cases in patients, and no suicides or suicide attempts were
noted for the 1200 non-patient, experimental participants.
However, it is important when evaluating these data to con-
sider that only 44 of the 62 researchers queried by Cohen
returned survey results (Cohen, 1960; Novak, 1997). Although
Cohen and Ditman (1962) subsequently expressed misgivings
over the increased incidence of adverse effects due to the
increasing recreational use of LSD and some questionable clin-
ical practices, they maintained that when used under the proper
guidelines, LSD was an important tool for use in human
research (cf. Novak, 1997). McGlothlin and Arnold (1971)
reported one case out of 247 individuals who received LSD in
either experimental or psychotherapeutic studies in which an
LSD-related psychotic reaction lasting more than 48 h
occurred. That single case was a patient who received repeated
LSD administrations in a psychotherapeutic context. Although
very rare, care must be taken to minimize the risks of such an
episode. The volunteer selection guidelines, addressed in a later
section, will be the key factor in minimizing the risk of pro-
longed psychosis in human hallucinogen research studies.
Some clinical observations suggest the possibility that
unconscious psychological material may be activated during
hallucinogen sessions, and that such material, if not properly
worked through and psychologically integrated, may lead to
psychological difficulties of a non-psychotic nature, such as
negative emotions and psychosomatic symptoms, lasting
beyond the session (e.g. McCabe, 1977; Grof, 1980). Although
these observations have not been examined experimentally,
they deserve consideration. As suggested in our subsequent
discussion of volunteer-monitor interactions, we believe that
the strong interpersonal support from session monitors before,
during and following sessions will minimize any enduring
untoward psychological effects.
Lasting perceptual abnormalities
Another potential risk of hallucinogen administration is hallu-
cinogen persisting perception disorder (HPPD). In order to
meet DSM-IV-TR criteria for this disorder, a hallucinogen
user must re-experience perceptual effects similar to those expe-
rienced under acute hallucinogen action after cessation of
hallucinogen use, these effects must be clinically distressing or
impair functioning, and the effects must not be caused by a
medical condition or be better explained by another psychiatric
disorder or hypnopompic hallucinations (American Psychiatric
Association, 2000). The incidence of HPPD is unknown,
although it is thought to be very uncommon given the rela-
tively few cases reported out of the millions of hallucinogen
doses consumed since the 1960s (Halpern and Pope, 2003).
Although the term ‘flashback’is sometimes used interchange-
ably with HPPD, the former term is often used to describe any
brief perceptual effects reminiscent of acute hallucinogen
effects but occurring beyond acute hallucinogen use, usually
in the absence of clinical distress or impairment (Lerner,
et al., 2002). Indeed, many illicit hallucinogen users report
some brief visual abnormalities occurring after acute hallucino-
gen effects, but only for a small minority of users are these
effects troubling or impairing enough to be considered clini-
cally significant or warrant the diagnosis of HPPD (Lerner,
et al., 2002; Baggott, et al., 2006). Many illicit users regard
such sub-clinical effects as benign and pleasurable (Strassman,
1984; Lerner, et al., 2002; Frecska and Luna, 2006). Impor-
tantly, the incidence of HPPD or other perceptual abnormali-
ties appears to be much lower in therapeutic or research
contexts with careful screening and preparation than in the
context of illicit recreational use, which may include the con-
founds of polydrug use and unscreened psychiatric disorders
(Cohen, 1960; McGlothlin and Arnold, 1971; Strassman,
1984; Halpern and Pope, 2003). Because such perceptual
abnormalities are poorly understood, researchers administering
hallucinogens to human volunteers should probe for perceptual
disturbances in follow-up contact.
Guidelines for safety
The guidelines that follow are intended to support the safe
administration of high doses of hallucinogens to human volun-
teers while minimizing potential adverse reactions. Although a
previous paper outlined methodological issues relevant to the
study of hallucinogens in humans (Gouzoulis-Mayfrank,
et al., 1998b), safety issues were not the primary focus of that
paper. The present paper substantially complements this previ-
ous work by providing a more detailed discussion of safety
concerns. Issues relevant to the conduct of human research
with drugs of abuse in general have been well described
(Fischman and Johanson, 1998). The present guidelines extend
and complement the recommendations of Fischman and
Johanson (1998) for high-dose hallucinogen research. For
some domains, such as volunteer selection, volunteer prepara-
tion, and the interactions between the volunteer and study
personnel, the proposed criteria are substantially more exten-
sive than those presented by Fischman and Johanson (1998)
and those routinely used in human behavioural pharmacology
because these domains appear to require even greater attention
for hallucinogens than for other classes of psychoactive drugs.
Although particular aspects of the proposed guidelines may be
debatable, it is hoped that this paper will encourage such dis-
cussion while conveying the general themes and major domains
of concern in human hallucinogen research. The proposed
guidelines may serve as a helpful starting point for investiga-
tors planning to conduct human hallucinogen research.
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Selection of volunteers
There are two main domains of consideration for volunteer
selection. First, selection criteria may be methodological in
nature and involve the specific research questions being
explored. Second, which is the focus of this manuscript, is
safety-related selection criteria. In our studies at Johns Hopkins,
participants must be in good general health as assessed by
detailed medical history, physical examination, 12-lead ECG,
blood chemistry profile, haematology and urinalysis. Pregnant
women or those not practicing effective means of birth control
are excluded. Relevant to general medical screening, classical
hallucinogens moderately increase pulse and both systolic and
diastolic blood pressure (Isbell, 1959; Wolbach, et al., 1962b;
Strassman and Qualls, 1994; Gouzoulis-Mayfrank, et al., 1999;
Passie, et al., 2000; Griffiths, et al., 2006). Therefore in our stud-
ies of psilocybin to date, volunteers have been excluded if resting
blood pressure exceeded 140 systolic and 90 diastolic (mmHg),
averaged across four assessments on at least two separate days.
Using these screening parameters with 54 participants to date,
no psilocybin session has resulted in blood pressure increases
considered medically dangerous, and we have never needed to
administer an anti-hypertensive medication in response to psilo-
cybin effects. Modification of these limits may be considered in
future studies if safety continues to be observed under these
parameters.
Certain medications may alter the effects of a hallucinogen
and, therefore, individuals taking these medications should be
excluded from participation. Specifically, chronic administration
of tricyclic antidepressants and lithium (Bonson and Murphy,
1996), and acute administration of serotonin reuptake inhibitors
(Fiorella, et al., 1996) and the antipsychotic medication haloper-
idol (Vollenweider, et al., 1998) have been shown to potentiate
hallucinogen effects, and therefore participants’use of these
represents a safety concern. Chronic administration of serotonin
reuptake inhibitors (Stolz, et al., 1983; Strassman, 1992; Bonson,
et al., 1996) and monoamine oxidase inhibitors (Bonson and
Murphy, 1996) have been shown to decrease sensitivity to
hallucinogens, and therefore participants’use of these represents
a scientific concern. We also advise investigators to include
questions concerning over-the-counter dietary supplements in
addition to prescription medications when probing medication
history, and to exclude those taking potentially problematic sub-
stances (e.g. 5-hydroxytryptophan and St John’sWortmay
affect serotonergic function, and, therefore, it is appropriate to
exclude individuals currently or recently taking these products).
It should also be noted that administration of ayahuasca (which
contains monoamine oxidase inhibitors in addition to DMT) to
individuals taking serotonin reuptake inhibitors may lead to a
severe serotonin syndrome reaction (Callaway and Grob, 1998).
Psychiatric screening criteria are important for minimizing
the already low chances of precipitating a longer term psychotic
reaction by hallucinogen administration. Thorough psychiatric
interviews (e.g. SCID; First, et al., 2001) should be conducted
to identify contraindicated psychological functioning or history.
In our research, individuals are excluded who have a current or
past history of meeting DSM-IV criteria for schizophrenia or
other psychotic disorders (unless substance-induced or due to a
medical condition), or bipolar I or II disorder, which are the
most important conditions to exclude for ensuring safety. We
also exclude those with a first or second-degree relative with
these disorders. There is considerable evidence from family,
twin and adoptive studies that genetic factors make a robust
contribution to the aetiology of schizophrenia, with genetic fac-
tors established as relevant to some, perhaps all cases (Buchanan
and Carpenter, 2005). In fact, data indicate that there is approx-
imately a six-fold greater chance of developing schizophrenia in
second-degree relatives of individuals with schizophrenia (Patel,
et al., 2003). Other investigators have also excluded individuals
scoring high on the personality traits of rigidity and emotional
lability on the grounds that these have been significantly associ-
ated with negative experiences during hallucinogen action and
during non-pharmacologically induced altered states of con-
sciousness (Dittrich, 1993; Hasler, et al., 2004).
Depending on the nature of the study, it may be appropriate
to exclude those with other psychiatric disorders as well. Unless
the research study is designed to specifically address a question
relevant to a specific psychiatric disorder, our advice is to select
a population that is psychiatrically healthy. This strategy is
warranted because the effects of hallucinogens may potentially
interact with various psychiatric disorders. Furthermore,
including volunteers with psychiatric disorders may increase
the chances that symptoms from such disorders may inadver-
tently be misattributed to hallucinogen action. For example,
our recent studies with healthy volunteers have excluded volun-
teers with a current or a recent past history (e.g. within the last
5 years) of alcohol or drug dependence (excluding caffeine and
nicotine) or major depression, and volunteers with current
obsessive-compulsive disorder, dysthymic disorder, panic disor-
der, dissociative disorder, anorexia nervosa or bulimia nervosa.
Recent and current studies have investigated therapeutic
applications of psilocybin for psychiatric disorders (Grob,
2005; Moreno, et al., 2006). Because preliminary reports have
suggested safety, studies examining therapeutic indications are
likely to continue. These studies target for participation volun-
teers with disorders that would normally be excluded from
non-treatment studies. Therefore, additional considerations
are appropriate for such studies. For example, in a study of
hallucinogen-assisted therapy for depression or anxiety, indivi-
duals should be excluded whose symptoms of depression or
anxiety are sufficiently severe to warrant immediate treatment
with medication (e.g. due to suicidal ideation). In addition,
clinical treatment studies may choose to lift restrictions on
relatively minor non-target psychiatric disorders that would
be excluded in studies with healthy volunteers. For example,
a study of hallucinogens in the treatment of anxiety related to
cancer might choose to allow the inclusion those with comor-
bid dysthymic disorder or mild obsessive-compulsive disorder.
Investigators should examine the relevant evidence when
considering lifting specific exclusions, proceed cautiously,
and implement any supplemental safeguards that might be
appropriate for such exceptions.
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Study personnel
It is difficult to overemphasize the importance of the interper-
sonal atmosphere created by study staff in influencing a volun-
teer’s response to a hallucinogen. Most critically, this applies to
the interpersonal environment created by the actual session
monitors (Leary, et al., 1964; Masters and Houston, 1966).
We use the term ‘monitor’to refer to the staff members, who
will be with the participant in the session room during the
course of hallucinogen action. The monitors should be knowl-
edgeable about the medical and psychological markers of
potential adverse reactions to the drug. Furthermore, monitors
should have significant human relation skills and be familiar
with descriptions of altered states of consciousness induced by
hallucinogens. Personal experience with techniques such as
meditation, yoga or breathing exercises may also prove to be
helpful in facilitating empathy for volunteers who experience
altered states of consciousness during hallucinogen action.
The lead monitor for each participant in the Johns Hopkins
studies to date has been a clinical psychologist or a clinical
social worker. However, we believe that clinical sensitivity
(e.g. empathy, respect) is likely more important than formal
degrees when considering monitor qualifications.
We recommend the presence of at least two monitors during
hallucinogen administration sessions so that the volunteer will
never be alone should one monitor need to briefly leave the
session room (e.g. to the restroom). For each participant in
the Johns Hopkins studies, we have specified a primary moni-
tor (who takes the lead in participant interactions) and an assis-
tant monitor, with differing required levels of involvement for
the two monitors during volunteer preparation (see Preparation
of volunteers section below). In prior research into potential
treatment applications of hallucinogens, the presence of both
genders in the monitoring team has been recommended (Grof
and Halifax, 1977; Grof, 1980; Kurland, 1985). Having both
genders present may foster feelings of security. In the Johns
Hopkins studies, we have followed this recommendation when
possible, but also have conducted sessions in which the primary
and assistant monitors were of the same gender as the volun-
teer. We would counsel against both members of the monitor-
ing team being the opposite gender of a volunteer, unless there
is a staff member of volunteer’s gender who has established
some rapport with the volunteer in advance, and who can
quickly be summoned to assist should support be needed in
the restroom. For studies that are intended to maximize the
potential for mystical-type experience during hallucinogen
administration, an additional valuable monitor characteristic
may be her or his ability to interact with and relate to the
participant concerning spiritual issues (e.g. Moss and Dobson,
2006; Council on Spiritual Practices, 2001).
Although the volunteer’s interactions with the monitors are
of paramount importance, all individuals at the study site
having contact with the volunteer on or before the session
day may influence a volunteer’s reaction to a hallucinogen.
Pre-session negative mood consisting of anxiety or depression
has been shown to significantly predict anxious or other
negative experiences during the session (Metzner, et al., 1965).
Strassman (2001) reported that a visiting medical student’s
unexpected interaction with a volunteer before the session
may have contributed to an adverse event resulting in the vol-
unteer leaving the study site under the influence of psilocybin.
To the degree possible, investigators should work with all
personnel that the volunteer may encounter (e.g. receptionist,
building security, nurses) to ensure that volunteers are treated
with courtesy and respect. For example, in the Johns Hopkins
studies, a research staff member other than the study monitors
meets with the volunteer in the morning and administers a few
pre-session questionnaires and manages other logistics. This
staff member should be friendly, welcoming and compassion-
ate, as he or she inquires as to the volunteer’s current
emotional and physical well-being (e.g. recent sleeping history,
interpersonal or work stressors, anticipation of session, adher-
ence to study dietary and medication/drug restrictions). The
staff member should maintain a positive social rapport with
the volunteer to reduce the likelihood of adverse psychological
reactions during the session and to gain accurate information
on the volunteer’s condition so that other study staff may be
notified if there is any potential reason to postpone or cancel
the session (e.g. if the volunteer is experiencing a particularly
stressful life event or is feeling ill). If any staff member treats
the volunteer disrespectfully or coldly (i.e. ‘like a guinea pig’),
this may negatively influence the volunteer’s psychological
state and subsequent hallucinogen experience. We recognize
that treating volunteers respectfully is an ethical imperative
for all human research. However, with hallucinogen adminis-
tration research, the importance of this mandate is even more
compelling given the powerful influence of set and setting on
hallucinogen effects. Therefore, we recommend providing
additional attention to volunteer rapport beyond what is cus-
tomary in general human behavioural pharmacology practice.
Physical environment
The physical environment during hallucinogen sessions is
extremely important for ensuring safety for volunteers in two
respects. First, an aesthetically pleasing environment may
decrease the probability of acute psychological distress. The
Johns Hopkins hallucinogen research projects use a living
room-like setting (Figure 1). The furniture is comfortable and
is atypical for a research laboratory or medical office setting.
An overly ‘clinical’environment with an ‘antiseptic’look (e.g.
white walls, extraneous medical equipment, personnel in white
lab coats) may increase anxious reactions. Strassman (2001)
noted that the medically oriented environment in which his
DMT studies were conducted may have contributed to volun-
teers having unpleasant subjective experiences. For example,
some volunteers reported vivid and realistic experiences of
being medically examined by extraterrestrials. It has also been
noted that many of the potentially unpleasant physical reac-
tions to hallucinogens (e.g. subjective changes in temperature,
difficulty in breathing, various bodily sensations) might be in
part psychosomatic in nature (Blewett and Chwelos, 1959),
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and therefore possibly more likely in settings evocative of med-
ical conditions (Masters and Houston, 1966). Some protocols
may require videotaping of sessions for scientific purposes.
Although there might be concern that videotaping could
increase self-consciousness or paranoia, we have no evidence
that this has occurred in the Johns Hopkins studies, in which
videotaping of sessions is routine.
Beyond the psychological importance of a comfortable,
relaxing environment, attention must be paid to the physical
safety of the environment. The environment should be designed
keeping in mind the perceptual changes and disorientation that
can occur under the influence of hallucinogens. Thus, any
potentially dangerous objects (e.g. furniture with sharp corners;
glass lamps) should be avoided. If there is a window in the
room, the investigators need to be confident that the volunteer
could not exit the window if in a delusional state. Additionally,
the session room should not have a telephone, and the partici-
pant should surrender her or his cellular telephone before the
session. Not only may an incoming telephone call be distract-
ing or alarming while under the influence of a hallucinogen,
but it may also represent a safety risk, as Strassman (2001)
has reported a case in which a participant used a session
room telephone to call a companion, which culminated in the
two fleeing the study site. Having a private restroom located
near the session room would be ideal for volunteer use during
the session. A shared restroom may be used if the monitors
ensure that the volunteer does not interact with non-study
personnel while going to the restroom (more details under the
section: Conduct of hallucinogen administration sessions). Of
course, most research laboratories do not provide the ideal
physical environment. Thus, resourcefulness and ingenuity
may be necessary to convert a less than ideal location into a
relaxing and secure environment.
Preparation of volunteers
As with any human research with psychoactive drugs, volun-
teer preparation at the earliest stages must include a thorough
review of the consent form, which should include in plain
language the range of experiences that may result from halluci-
nogen administration, including changes in perception, sense of
time and space, and emotion (possibly including anxiety, fear,
panic and paranoia). Relative to other drug classes, the subjec-
tive effects of hallucinogens are likely more difficult to describe
to a naïve volunteer; therefore, additional time may be neces-
sary to fully discuss these potential effects with volunteers. The
consent form should also include the approximate timecourse
of the drug, the state of knowledge concerning its toxicity pro-
file, and its status as an experimental drug. In addition, the
consent form should state that there is a relatively small risk
of adverse effects that last for hours to days after the hallucino-
gen session. These include mood disorders (such as depression),
psychotic disorders and anxiety disorders. It should also state
that there are rare reports in which hallucinogen exposure
appears to cause, accelerate or precipitate the onset of signifi-
cant or lasting psychiatric illnesses such as psychoses and
intermittent or persisting visual perceptual abnormalities
(‘flashbacks’, HPPD).
The next step in volunteer preparation is to conduct a series
of meetings between the monitors and volunteer to build
rapport and trust. The relationship between the monitors and
the volunteers should be well established by the time of the first
session (Masters and Houston, 1966). In the Johns Hopkins
studies, there are at least eight contact hours over the course
of at least four meetings, usually over a 1-month period. One
Figure 1 The living room-like session room used in the Johns Hopkins
hallucinogen research studies. Aesthetically pleasing environments such as
this, free of extraneous medical or research equipment, in combination
with careful volunteer screening, volunteer preparation and interpersonal
support from two or more trained monitors, may help to minimize the
probability of acute psychological distress during hallucinogen studies.
For studies that investigate potential therapeutic effects or the
phenomenology of introspective hallucinogen experiences, the use of
eyeshades and headphones (through which supportive music is played)
may contribute to safety by reducing the distractions of environmental
stimuli and social pressures to verbally interact with research personnel.
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of these preparatory meetings should be conducted in the room
in which the hallucinogen is to be administered, to familiarize
the participant with the physical environment. The primary
monitor meets with the volunteer during all of these meetings,
while the assistant monitor is required to be present on at least
one occasion. It is important that the assistant monitor, in
addition to the primary monitor, has developed a trusting
relationship with the volunteer because this assistant monitor
will be the only person in the session room with the volunteer
if the primary monitor needs to leave briefly.
During these preparatory meetings, the monitors discuss
meaningful aspects of the volunteer’s life. The main purpose
of the participant–monitor meetings is to develop rapport and
trust, which we believe helps minimize the risk of fear or anxi-
ety reactions during the hallucinogen session. This typically
includes discussions of the volunteer’s childhood, romantic
life, current relationships with family and friends, and the
volunteer’s philosophical and/or spiritual beliefs. Reviewing
personal history and feelings may be important for two rea-
sons. First, this discussion helps establish a significant level of
trust. The interaction should convey that all aspects of the per-
son are welcome, from the petty to the noble, from embarrass-
ments to achievements and from sorrow to joy. By the time of
the hallucinogen session day, the volunteer will ideally feel
completely comfortable with the monitors, reducing the likeli-
hood of paranoia (e.g. feeling that the monitors are trying to
control her or his mind, or have deceived the volunteer about
the nature of the study). Second, related personal material may
‘emerge’under the effects of the hallucinogen. That is, the vol-
unteer may experience intense thoughts, feelings and visions
related to his or her personal history or world-view. Knowing
about the volunteer’s life will allow the monitors to better
understand her or his session experience and help the monitors
in providing interpersonal support should strong emotions
arise. If it is felt that sufficient rapport and trust have not
developed during these monitor meetings, then either addi-
tional contact hours should be provided, or the volunteer’s par-
ticipation should be cancelled. A high dose of a hallucinogen
should not be administered to a volunteer if sufficient trust has
not been established. As with other forms of human research
involving the development of rapport and trust (e.g. clinical
trials involving psychotherapy), investigators should be careful
that this rapport and trust does not create a situation in which
the volunteer feels obligated to remain in the study. Volunteers
and monitors should be clear that participation is voluntary,
and that the participant will be fully supported if her or his
decision is to quit the study.
At some point during preparatory meetings, time must be
devoted to explain the study logistics. These should include
the timing of the session (e.g. what time to arrive at the labora-
tory if an outpatient study, what time the session is likely to
end), any restrictions on diet or contraindicated medicines,
drugs or nutritional supplements (e.g. if fasting or a low-fat
diet is required the morning before session), and any require-
ments of other people (e.g. if a family member or friend is to
pick up the participant at the end of the session).
This discussion should also include thorough descriptions of
study procedures, to the degree allowable by blinding issues.
For example, if cognitive or memory tests are to be performed,
or questionnaires are to be answered, the participants should
be aware of these requirements. If physiological measures,
such as blood pressure, are to be taken during the time of
drug action, this also should be explained. The activities during
hallucinogen action will naturally depend on the scientific
questions under investigation. Whatever the nature of the
experiment after hallucinogen administration, the scenario
should be thoroughly discussed with the volunteer in prepara-
tion. In some cases, such as with brain imaging research, it may
be helpful for volunteers to be run through a preliminary
research session to familiarize them with the equipment and
procedures. Some studies have conducted an initial non-blind
hallucinogen administration session in which safety measures
are assessed before subsequent blinded sessions to, among
other reasons, acquaint volunteers with the effects of the drug
before the introduction of additional, potentially anxiety pro-
voking measures (e.g. blood draws) (Strassman and Qualls,
1994; Strassman, et al., 1994, 1996).
The preparation of the volunteer should involve a detailed
discussion of the possible range of experiences that may be
encountered after hallucinogen administration. This includes
the typical onset and duration of the drug(s) under investiga-
tion. Preparation involves discussion of the various potential
physical sensations, such as nausea or heightened awareness
of physiological processes, such as breathing and heartbeat.
Volunteers are encouraged to trust that their bodies will
continue to function properly regardless of such sensations,
and that these bodily processes will continue without the
volunteers’volitional control.
The major categories of potential psychological experiences
during hallucinogen action should be discussed with the partic-
ipant. The range of subjective experience under hallucinogens
can be remarkably broad (Blewett and Chwelos, 1959;
Richards, 1980; Masters and Houston, 1966; Strassman, 2001;
Nichols, 2004; Stolaroff, 2004). This range of experiences
includes perceptual changes, such as visual illusions, intensifi-
cation of colours, proprioceptive changes (e.g. one’s body may
feel gigantic or tiny), and synesthesia (e.g. seeing sounds or
hearing colours). Another type of possible experience is the
alteration of emotions, such that emotions of either a positive
or negative nature may be greatly intensified, yielding experi-
ences that may range from euphoria to despair. Another cate-
gory of possible effects involves changes in the sense of time
and space. At the extremes, time and/or space may be experi-
enced as infinite or nonexistent. Other experiences may include
thoughts, feelings or insights concerning one’s personal history
(e.g. revisiting childhood memories) or current life circum-
stances (e.g. relations with loved ones), highly symbolic experi-
ences (e.g. involving religious symbols, animals, etc.), and
experiences described by some to be of a mystical or spiritual
nature. Importantly, it should be emphasized that these experi-
ences may consist of much more than the participant subjec-
tively observing internal and external events. Rather, the effects
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may involve a profound change in one’s sense of self, such that
one feels as if he or she is merging into the surrounding
environment or the entire universe (Schultes, et al., 2001). The
individual may temporarily experience a complete loss of
subjective self-identity, a phenomenon sometimes referred to
as ‘ego loss’or ‘ego death’(e.g. Leary, et al., 1964; Grof and
Halifax, 1977; Grof, 1980). While a detailed discussion con-
cerning the range of possible hallucinogen effects will enhance
safety by psychologically preparing the participant for the
unique and often intense effects of a hallucinogen, it may also
serve to undermine the blind. That is, such preparation may
train the participant on how to identify a hallucinogen by
its effects. Nonetheless, the primary concern must be the parti-
cipant’s safety. Therefore, researchers must minimize the
potential for unblinding by manipulating other aspects of the
experimental design, such using hallucinogen-naïve participants
or the use of an active placebo (e.g. Griffiths, et al., 2006).
The volunteers should be given guidance on how to handle
difficult hallucinogen experiences. Whether the disturbance
consists of frightening illusions or internal imagery, difficult
thoughts and feelings about some past or present personal
issue, or anxiety related to a radical change in sense of self
(e.g. temporary loss of self-identity), the volunteer is encour-
aged to mentally surrender to the experience, trusting that her
or his usual state of consciousness will return when the drug
effects resolve (Blewett and Chwelos, 1959; Masters and
Houston, 1966; McCabe, 1977). For example, if the participant
experiences disturbing internal imagery of a demon or monster,
he or she is encouraged to mentally approach the figure and
interact with it (e.g. imagine asking the figure why it has
appeared), rather than attempt to flee from the disturbing
imagery. The participant should be alerted that sometimes
people experience extremely convincing sensations of dissolv-
ing, melting, exploding and so forth, and that the best way to
deal with all such situations is to surrender to the experience,
subjectively allowing oneself to dissolve, melt or explode. Simi-
lar advice applies to physical symptoms such as nausea; for
example, participants may be encouraged to ‘dive in’to their
stomachs, which may alleviate the nausea, as it has been sug-
gested anecdotally that nausea and other somatic discomforts
may in part be of a psychosomatic nature (Blewett and
Chwelos, 1959; Masters and Houston, 1966).
The preparation of volunteers for hallucinogen administra-
tion will require balancing the ethical requirements to prepare
the volunteer for the potentially powerful psychological effects
of hallucinogens, with the scientific concern not to bias the
volunteer with respect to the dependent variables. This is
especially true because classical hallucinogens have been
shown to increase suggestibility in an experimental model
involving body sway (Sjoberg and Hollister, 1965; Middlefell,
1967), and suggestibility has been proposed as a potential
mechanism of the possible therapeutic efficacy of hallucinogens
(Dobkin de Rios, et al., 2002; Barbosa, et al., 2005). That is,
one could argue that examples conveyed during preparation
are then experienced during the session only due to an
increased level of suggestibility during hallucinogen action.
Increased suggestibility would seem to be of greatest concern
as a confound when investigating the phenomenology of sub-
jective hallucinogen-occasioned experience (e.g. the study by
Griffiths, et al. (2006), demonstrating that psilocybin can occa-
sion mystical-type experiences under supportive conditions). In
the study by Griffiths, et al. (2006), although experiences of a
spiritual variety were included among the range of possible
effects conveyed in preparation, the monitors emphasized that
these experiences were not the only variety of interesting or
valuable effects that might occur. Specific categories of
mystical-type experience to be assessed in measures were not
discussed. In the Johns Hopkins studies, we have not encouraged
participants to read the diverse and widely varying published
accounts of hallucinogen effects as part of their preparation,
because this may introduce compelling idiosyncratic expecta-
tions. Our research has proceeded safely by delivering all such
preparatory information to participants verbally during pre-
session meetings with monitors. Researchers will need to design
studies such that a maximum amount of preparation is provided
for safety reasons, while not confounding the particular hypothe-
ses being studied. Furthermore, controlled studies should ensure
that the unique preparation methods and research environment
qualities described herein are in place, under double-blind condi-
tions, for both hallucinogen and placebo groups (or conditions).
For example, in the study by Griffiths, et al. (2006), the use of
identical procedures under double-blind conditions for psilocybin
sessions and the active placebo (a high dose of methylphenidate)
sessions permitted a reasonable degree of control over
suggestibility.
Conduct of hallucinogen administration sessions
As with research with many other psychoactive drugs, a physi-
cian should be available during hallucinogen sessions, should
any untoward medical complications arise. Furthermore, med-
ication for the treatment of acute hypertension (e.g. intrave-
nous labetalol) should be immediately available in the event
that blood pressure exceeds predetermined safety parameters.
Adverse psychological reactions to hallucinogens will be
minimized when studies are conducted under conditions that
provide strong interpersonal support to the participants
(Blewett and Chwelos, 1959; Chwelos, et al., 1959; Pahnke,
1969; Masters and Houston, 1966). The monitors should care-
fully observe the participant and be vigilant for signs of psy-
chological distress. If the volunteer needs to walk to complete
study tasks or to go to the rest room, the monitors should stand
close by to assist by gently holding an arm or shoulder. Even
with high doses of hallucinogens, individuals do not typically
show substantial motor impairment, and will likely be able to
ambulate without considerable difficulty (with the exception
of hallucinogens such as parenteral DMT with abrupt effects
and short duration of action). However, perceptual and propri-
oceptive effects may make walking disorienting, which is why
gentle guidance may be helpful. One of the monitors should
always be present in the session room with the participant.
Because the session monitors will have developed rapport and
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trust with the participant, they should be the only people to
interact with the volunteer during the course of hallucinogen
action, barring any non-routine event (e.g. fire alarm, medical
intervention by a specialist). Individuals who are anticipated to
have contact with the volunteer during the course of hallucino-
gen action (e.g. nurse, physician) should have at least met with
the volunteer once prior to session to develop some degree of
rapport and trust.
For all but the shortest acting hallucinogens (e.g. parenteral
DMT), the participant is likely to need to use the restroom at
some point while experiencing hallucinogen effects. If a private
restroom is not available, then study staff should escort the
volunteer to assure that no one is in the restroom. Either the
restroom door needs to have no lock, or study staff should
have a key readily available if needed. Cohen (1960) reported
a case in which a depressed patient who had been administered
LSD barricaded himself into a room to attempt suicide. In the
Johns Hopkins studies, sessions are conducted in a room
located on the third floor of a research facility. The session
room itself has a private restroom just outside of the session
room. During sessions, the volunteer is closely escorted to the
restroom and a session monitor waits just outside the restroom
to be available if the volunteer should encounter any difficul-
ties. Furthermore, waiting in this area outside the restroom
allows the monitors to ensure that the volunteer does not exit
the research site. Any attempt by a disoriented volunteer to
leave the session area would be met with compassionate but
firm direction to return to the session room.
Serious attention must be devoted to the possibility of
volunteers trying to leave the study site under the influence of
a hallucinogen. Walter Pahnke’s (1963) dissertation study
(known as the ‘Good Friday Experiment’) examined the ability
of a high dose of psilocybin to occasion mystical experiences by
administering either psilocybin or placebo (randomly assigned)
to seminary students in a small, basement chapel into which a
Good Friday service from the main sanctuary was broadcast.
A retrospective investigation conducted over 25 years after the
original experiment revealed that two volunteers left the chapel
under the influence of psilocybin (Doblin, 1991). One of these
volunteers reported feeling imprisoned in the chapel and left
the chapel during a portion of the experiment. The other vol-
unteer abruptly left the chapel believing that God had chosen
him to immediately announce to the world the dawning of an
age of peace (Roberts and Jesse, 1997; Smith, 2000). This vol-
unteer was apprehended by the research staff and administered
the antipsychotic agent chlorpromazine after efforts to calm
him were unsuccessful (Doblin, 1991; Roberts and Jesse,
1997; Smith, 2000). Strassman (2001) also reported an incident
in which a participant experiencing the full effects of a high
dose of psilocybin evaded the research staff and left the
research site. Fortunately, the participant’s spouse monitored
the participant and no one was injured.
The risks of allowing a research volunteer experiencing the
effects of a hallucinogen to leave the study site are significant.
For example, in a bewildered or delusional state, the person
might walk into traffic or attempt to drive. Although many
hallucinogen users maintain reasonable control while under
the influence of hallucinogens, panic or delusional reactions
to hallucinogens have in rare circumstances resulted in tragic
consequences, such as jumping out of windows (Keeler and
Reifler, 1967; Reynolds and Jindrich, 1985; Reitman and
Vasilakis, 2004; O’Brien, 2006). Interestingly, the volunteer
who fled Strassman’s (2001) study site on psilocybin was a
carefully screened, experienced LSD user. Therefore, it is
imperative for safety reasons that the study site environment,
session procedures and participant preparation all minimize the
chance of a volunteer leaving the study site.
Strategies for handling non-routine scenarios should be
considered. For example, how are study monitors and the
volunteer expected to respond in the event of a fire alarm or
fire? On the single occasion at Johns Hopkins in which a fire
alarm sounded during a session, the two study monitors closely
escorted the volunteer outside, making sure to minimize con-
tact with other individuals. The three of them walked to a
nearby quiet area with an attractive landscape and enjoyed
the scenery until the volunteer and monitors could return to
the building. The monitors encouraged the participant to view
the occasion as an opportunity to enjoy the natural world out-
doors (something normally unavailable during sessions), rather
than as an impediment to having a successful session. If any
non-routine events occur, the monitors should maintain con-
tact with the volunteer throughout.
If participants become anxious during the course of halluci-
nogen action, it is now widely recognized that the appropriate
first response is to provide strong personal support and reassur-
ance (O’Brien, 2006). This primarily includes interacting with
the volunteer in a comforting and reassuring manner. If the
volunteer is behaving anxiously and a negative psychological
reaction seems to be escalating, the monitors should convey a
solid sense of security and calm, while empathizing with what
may be an incredibly intense and unpleasant experience.
Attempts to ‘talk down’the participant (i.e. the use of reality-
defining techniques to distract the participant from or
attenuate the altered state of consciousness) may be counter-
productive and aggravate a difficult reaction (McCabe, 1977).
Instead, participants should be reminded to surrender to the
experience. Appropriate forms of reassurance may include a
supportive touch to the arm or shoulder with verbal reminders
that the participant is in a research study, has taken the hallu-
cinogen, and that he or she will return to normal consciousness
in ‘a few minutes’or ‘a few hours’(or whatever the appropri-
ate estimate may be, depending on the specific drug under
study and when it was administered). During an intense
hallucinogen-occasioned experience when verbal interactions
may be of limited help, a powerful form of reassurance (some-
times called ‘interpersonal grounding’) is simply holding the
hand of the participant (McCabe, 1977). Many volunteers
report that during such experiences, a reassuring hand provides
an incredible sense of stability and connection. Monitors
should demonstrate this practice during preparation to normal-
ize hand holding during sessions.
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If volunteers have been appropriately screened and the
guidelines herein followed, reassurance should be sufficient to
diffuse acute psychological distress in the vast majority of
cases. For example, in recent studies in our laboratory, in
which we have administered high doses of psilocybin to
54 volunteers, reassurance has been sufficient to handle all
cases of acute psychological distress that have arisen. Although
pharmacological intervention is a last resort and should rarely,
if ever, be needed, medications should be readily available for
use if the need arise. For cases in which acute psychological
distress is insufficiently managed with reassurance alone, treat-
ment with a benzodiazepine anxiolytic is the pharmacological
intervention of choice (Abraham and Aldridge, 1993; Frecska
and Luna, 2006; O’Brien, 2006). In these cases, we recommend
a 10 mg oral dose of diazepam (Grinspoon and Bakalar, 1979),
although oral doses of 15–30 mg per hour or every few hours as
needed have been recommended for pharmacological treatment
of ‘bad trips’that do not respond to reassurance in emergency
department settings (Ungerleider and Frank, 1976). Because of
its high lipid solubility, diazepam has a more rapid onset, a
shorter time until peak plasma concentration and a shorter
duration of therapeutic action than many other benzodiaze-
pines including lorazepam, despite the fact that lorazepam has
a shorter elimination half-life (Greenblatt and Shader, 1985;
Funderburk, et al., 1988). Although the intravenous route
may be considered, the oral route is preferable because intrave-
nous injection procedures may further exacerbate the
participant’s anxiety. Moreover, antipsychotic medications
(e.g. risperidone, olanzapine) should be available in the event
that an adverse reaction escalates to unmanageable psychosis.
However, experienced clinicians have suggested that although
antipsychotic medications may reduce psychotic behaviour
through sedation, their use may be problematic because the
effects may be abrupt, unpleasant and intense and their use
may result in subsequent psychological problems (McCabe,
1977; Grinspoon and Bakalar, 1979; Grof, 1980). Furthermore,
pretreatment with the antipsychotic haloperidol has been
shown to exacerbate the psychosis-like effects of psilocybin
(Vollenweider, et al., 1998), suggesting that haloperidol should
not be used as a rescue medication. Although not approved for
use in the USA, ketanserin (a 5-HT
2A
antagonist) pretreatment
has been shown to attenuate psilocybin effects (Vollenweider,
et al., 1998), suggesting possible use as a rescue medication for
hallucinogen administration. Ultimately the decision to medi-
cate will depend on whether the monitors and responsible
physician judge that they are capable of maintaining the safety
of the volunteer and others without medical intervention.
Bringing the participant to the emergency department
represents an ultimate ‘last resort’in the treatment of a very
difficult (i.e. psychotic) reaction. However, medical evaluation
by well-meaning emergency department personnel, who are
inexperienced with hallucinogen effects can readily escalate
and prolong an adverse reaction. Therefore, all possible efforts
should be made to treat a difficult experience in the session
context, even if pharmacological intervention is required.
The conduct of the session will largely be based on the
particular research topics being studied. The research require-
ments of many types of studies will require the participants to
adhere to regimented testing conditions (e.g. cognitive tests,
memory tests, brain scans). In such investigations, interference
with procedures may be minimized by judiciously selecting
dose and the hallucinogen experience level required of volun-
teers. Adverse reactions will generally be more likely at higher
hallucinogen doses; however, adverse reactions can potentially
occur at any dose level. Experienced hallucinogen users may be
particularly appropriate participants for studies involving chal-
lenging conditions, such as remaining immobile for long peri-
ods in a confining brain imaging scanner. Regardless of experi-
ence level and dose, however, the possibility of psychological
adverse reactions exists whenever a hallucinogen is adminis-
tered. To the degree possible, investigators should attempt to
implement their scientific protocols as planned. However,
monitors should always be vigilant for potential adverse
psychological reactions. In the event of a significant adverse
psychological reaction, interpersonal support should be
provided even if it interferes with data collection. Clearly,
volunteer safety must take priority over scientific procedures.
In studies such as ours, in which participants are encouraged
to focus their attention inward by wearing eyeshades and
listening to music through headphones, our advice is for
monitors to occasionally probe the volunteer’s psychological
well-being (e.g. ask the volunteer, ‘Would you like to describe
where you find yourself?’) to ensure that the volunteer is not
experiencing significant anxiety and is in need of support.
For studies that investigate potential therapeutic effects or
the phenomenology of hallucinogen experiences (i.e. studies
that do not require participants to engage in research tasks dur-
ing the session), the employment of eyeshades and headphones
(through which supportive music is played) may contribute to
safety by reducing the distractions of environmental stimuli
and social pressures to verbally interact with research person-
nel. This may be especially important for volunteers who are
experiencing the effects of a hallucinogen for the first time.
Typically, we have kept eyeshades and headphones in place
for most of the session. In the latter hours of the session some
time is spent with the volunteer sitting on the couch, interacting
without eyeshades and headphones, although music may still
be played through speakers to provide nonverbal structure
and continuity. As a whole, we encourage our participants to
‘collect experiences’to discuss after the drug effects have
abated, and discourage attempts to analyse material or com-
municate excessively while the atypical states of consciousness
are still occurring.
After the effects of the hallucinogen have resolved, the par-
ticipant should either be released into the care of a friend or
family member or required to stay overnight at the research
site for monitoring. If participants are released from the study
site after the session, they should be instructed not to drive an
automobile or engage in any other potentially dangerous
activity for the remainder of the day. At Johns Hopkins,
volunteers are released into the care of a friend or family
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member, who has been appropriately oriented by our staff to
be available to emotionally support the participant, but also to
provide space (i.e. be in another room) if the participant feels
the need to be alone. We have also given the participant the
primary monitor’s pager number to call if he or she feels the
need for support that evening. Of the 54 volunteers tested at a
high psilocybin dose to date, no one has paged the monitor,
although volunteers do seem to appreciate this opportunity
for additional support.
Post-session procedures
After the session, safety monitoring should continue in the
form of one or more post-session meetings (typically the next
day) between the primary monitor and participant to ensure
psychological stability and provide an opportunity for the
volunteer to discuss thoughts or feelings from the session. As
with any acute, intense positive or negative emotional experi-
ence, participants often feel the need for, and seem to benefit
from, additional time for reflecting on the novel thoughts and
feelings that may have arisen in the session. Given the poten-
tially intense and unusual psychological nature of hallucinogen
effects, the volunteer may have difficulty discussing the experi-
ence with others in her or his life. Because the monitors were
present during the session when the hallucinogen effects were
experienced and have knowledge of a broad range of reported
phenomena during drug action, the volunteer may feel more
comfortable discussing her or his experience with the monitors
than with others. This follow-up contact also allows the assess-
ment of any potentially persisting adverse effects, including
perceptual abnormalities. More than one post-session meeting
may be necessary if the volunteer is experiencing psychological
difficulty concerning thoughts and feelings encountered during
the session. Of the 54 volunteers tested with a high dose of
psilocybin at Johns Hopkins to date, none has shown evidence
of persisting psychosis or psychological problems related to
their sessions, and all have returned to their normal daily activ-
ities. If the primary session monitor is not a clinically trained
psychologist or psychiatrist, it is prudent for research teams to
have available for consultation a clinically trained psychologist
or psychiatrist familiar with altered states of consciousness,
who can work with patients who appear to have developed
psychological difficulties stemming from hallucinogen
administration.
Concluding remarks
After a decades-long period of dormancy in response to the
sensationalism surrounding the nonmedical use of hallucino-
gens during the 1960s, human hallucinogen research has
resumed in the USA and Europe, and is now beginning to
address a variety of important basic research questions as well
as potential therapeutic applications (Nichols, 2004). In light of
the unusual history of restriction on human research with this
class of compounds, it is critical for investigators to implement
appropriate and conservative safeguards. With such safeguards
this class of compounds can be studied safely in humans.
Careless research that lacks attention to the unique risk profile
of hallucinogens may not only endanger the safety and well-
being of the research participants, but may also jeopardize
future human research with these scientifically fascinating com-
pounds. On the other hand, carefully conducted research that
respects hallucinogens’unique and often powerful psychologi-
cal effects may potentially inform the treatment of various
psychiatric disorders, as well as lead to significant advances in
our understanding of perception, cognition, behaviour, the
psychology of religion and the biological underpinnings of
consciousness.
Acknowledgements
Support for preparation of this manuscript was provided by grants
from NIH (R01 DA03889), the Council on Spiritual Practices and
the Heffter Research Institute. We thank George Greer, MD,
Charles Grob, MD, Robert Jesse, Annie Umbricht, MD and Franz
Vollenweider, MD for helpful comments on previous versions of this
manuscript. We also thank the staff of the Johns Hopkins psilocybin
research studies, whose insights have contributed to these guidelines,
including Mary P. Cosimano, MSW and Brian D. Richards, Psy.D.
for their roles in screening volunteers and monitoring sessions, and
Lawrence P. Carter, PhD, Ryan K. Lanier, PhD, Benjamin McKay,
Chad J. Reissig, PhD, and Ryan G. Vandrey, PhD for their assistance
in monitoring sessions.
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