Neuropharmacology xxx (2017) 1e19

Contents lists available at ScienceDirect

Neuropharmacology
journal homepage: www.elsevier.com/locate/neuropharm

Invited review

Studies with psychedelic drugs in human volunteers

Edward.M. Sellers a, b, c, d, f, *, Myroslava K. Romach c, d, f, Deborah B. Leiderman e
a
Departments of Pharmacology and Toxicology, University of Toronto, Toronto, ON, Canada
b
Medicine, University of Toronto, Toronto, ON, Canada
c
Psychiatry, University of Toronto, Toronto, ON, Canada
d
Surgery, University of Toronto, Toronto, ON, Canada
e
CNS Drug Consulting, McLean, VA, USA
f
DL Global Partners Inc, Toronto, ON, Canada

a r t i c l e i n f o a b s t r a c t

Article history: Scientific curiosity and fascination have played a key role in human research with psychedelics along
Received 29 August 2017 with the hope that perceptual alterations and heightened insight could benefit well-being and play a role
Received in revised form in the treatment of various neuropsychiatric disorders. These motivations need to be tempered by a
31 October 2017
realistic assessment of the hurdles to be cleared for therapeutic use. Development of a psychedelic drug
Accepted 17 November 2017
for treatment of a serious psychiatric disorder presents substantial although not insurmountable
Available online xxx
challenges.
While the varied psychedelic agents described in this chapter share some properties, they have a range
of pharmacologic effects that are reflected in the gradation in intensity of hallucinogenic effects from the
classical agents to DMT, MDMA, ketamine, dextromethorphan and new drugs with activity in the
serotonergic system. The common link seems to be serotonergic effects modulated by NMDA and other
neurotransmitter effects. The range of hallucinogens suggest that they are distinct pharmacologic agents
and will not be equally safe or effective in therapeutic targets. Newly synthesized specific and selective
agents modeled on the legacy agents may be worth considering.
Defining therapeutic targets that represent unmet medical need, addressing market and commercial
issues, and finding treatment settings to safely test and use such drugs make the human testing of
psychedelics not only interesting but also very challenging.
© 2017 Elsevier Ltd. All rights reserved.

Contents

1. Introduction . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 00
2. Terminology . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 00
3. Scope of this chapter . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 00
4. Therapeutic studies . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 00
5. Scientific constraints on human psychedelic agent research . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 00
6. The Safe conduct of human studies with psychedelics . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 00
7. Choice of measures of psychedelic drug effects . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 00
8. Selected case studies . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 00
8.1. Lysergic acid diethylamide (LSD) . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 00
8.1.1. Pharmacokinetics . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 00
8.1.2. Pharmacodynamics . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 00
8.2. Psilocybin . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 00
8.2.1. Psilocybin pharmacokinetics . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 00
8.2.2. Pharmacodynamics . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 00
8.2.3. Phase II proof of concept studies . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 00

* Corresponding author. 78 Baby Point Crescent, Toronto, M6S 2C1, ON, Canada.
E-mail address: sellers.ed@gmail.com (Edward.M. Sellers).

https://doi.org/10.1016/j.neuropharm.2017.11.029
0028-3908/© 2017 Elsevier Ltd. All rights reserved.

Please cite this article in press as: Sellers, E.M., et al., Studies with psychedelic drugs in human volunteers, Neuropharmacology (2017), https://
doi.org/10.1016/j.neuropharm.2017.11.029
2 Edward.M. Sellers et al. / Neuropharmacology xxx (2017) 1e19

8.3. N, N-Dimethyltryptamine (DMT) . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 00

8.3.1. Pharmacokinetics and pharmacodynamics . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 00
8.4. Salvinorin A . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 00
8.4.1. Pharmacokinetics - animals . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 00
8.4.2. Pharmacodynamics e human . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 00
8.5. Ketamine . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 00
8.5.1. Pharmacokinetics . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 00
8.5.2. Pharmacodynamics . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 00
8.6. Methylenedioxymethamphetamine (MDMA) “ecstasy” . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 00
8.6.1. Pharmacokinetics . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 00
8.6.2. Therapeutic applications . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 00
8.7. Dextromethorphan . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 00
8.7.1. Pharmacokinetics . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 00
8.7.2. Pharmacodynamics . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 00
8.8. Lorcaserin . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 00
9. Practical and regulatory challenges . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 00
10. Future research . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 00
10.1. Need for understanding the neurobiology . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 00
10.2. Expand pharmacokinetics and pharmacogenomics . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 00
10.3. Need to meet modern safety standards . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 00
10.4. Need for comparative trials . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 00
10.5. Comparisons of psychedelic agents . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 00
10.6. Adjunctive psychotherapy . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 00
10.7. Dose ranging . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 00
10.8. Assessment of abuse potential . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 00
11. Conclusions . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 00
Disclosures . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 00
Supplementary data . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 00
References . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 00

” They were united by a fierce attachment to the belief that discuss the numerous practical and scientific challenges and not
psychedelic drugs, far from being a recreational diversion, have only the regulatory and legal obstacles.
the potential to enlighten, cure illness and change the way For the most part, the mechanism of action underlying the
people relate to one another and our planet.”(2017b) pharmacologic effects for most psychedelic substances is not
known. This is true even when a potential therapeutic benefit is
“The latest way to get high is toad licking. A popular lick victim:
posited or proposed. Their basic pharmacology is diverse and in-
the Colorado River Toad. When agitated, it secretes a halluci-
cludes complex agonist and partial agonist/antagonist actions on
nogenic chemical through its skin. But the party practice could
5HT2A, 5HT2C, 5HT1A, dopamine D₂, trace amine associate re-
be fatal - some toads emit a cardiac toxin”.(Anonymous, 2017)
ceptors 1 (TAAR), kappa receptors, various transporters (e.g., sero-
tonergic, dopaminergic, norepinephrine), intracellular messengers,
effects on gene expression and epigenetic regulators. Such a wide
1. Introduction range of pharmacologic mechanisms and targets raises the proba-
bility of unexpected acute and chronic off-target toxicity and an
Substances with psychedelic properties have been used for elevated risk of interactions with concurrent diseases and drugs
millennia in ceremonial and religious contexts as humans have that will vary for different psychedelics.
tried to interact with and gain insight into their personal social The innovative chemistry skills of those experimenting recrea-
context, consciousness and belief systems. This rich history has tionally with psychedelic substances has led to the illicit synthesis
been fostered and documented by social anthropologists, ethno- of many “designer” agents closely related to “classical” psyche-
botanists and chemists (Davis, 1996; Jacob and Shulgin, 1994; delics” such as LSD, mescaline, psilocybin (Sellers, 2017a). These
Naranjo et al., 1967). The enormous literature — a PubMed search compounds typically use an existing structure e.g., stimulant or
restricted to “psychedelic humans” and “hallucinogen humans” precursor as a starting point, and add substituents that result in
yields >11,800 references– attests to an enduring fascination for hallucinogenic or psychotomimetic effects. For example, mescaline
many with agents that can profoundly alter human perception. This is a ring substituted phenylethylamine ring structure (3, 4, 5-
interest, however, has not always been matched by the scientific trimethoxyphenethylamine) e a substructure that has spawned
rigor and methods used in other human pharmacology studies, thousands of variants of stimulants and perception-altering drugs
even when a therapeutic application is contemplated. Despite an (e.g., MDMA).
extensive and carefully compiled literature, cataloging and
describing hundreds of naturally occurring plants, extracts, purified 2. Terminology
chemicals and newly synthesized chemicals, most hallucinogen
research in humans has been conducted on a small number of From an historical perspective, “psychedelic” connotes agents
subjects and has been descriptive and uncontrolled. The relative that have a “mind-manifesting capability, revealing useful or
lack of rigorous human studies has been attributed to International beneficial properties of the mind”, inferring some potential thera-
and National restrictions on possession of and research with such peutic usefulness (Nichols, 2016; Osmond, 1957). Alternative
psychedelic compounds (Nutt et al., 2013). In this chapter, we operational criteria for establishing that a drug is hallucinogenic

Please cite this article in press as: Sellers, E.M., et al., Studies with psychedelic drugs in human volunteers, Neuropharmacology (2017), https://
doi.org/10.1016/j.neuropharm.2017.11.029
 Edward.M. Sellers et al. / Neuropharmacology xxx (2017) 1e19
include: in proportion to other effects, changes in thought,
perception, and mood should predominate; intellectual or memory
impairment should be minimal; stupor, narcosis, or excessive
stimulation should not be an integral effect; autonomic nervous
system side effects should be minimal; and “addictive craving”
should be absent (Hollister, 1968). An additional feature is that the
primary effects occur with specificity and selectivity even at low
doses. This characterization offers scope for a wide range of agents
to be included.
“Psychedelic” agents comprise a large and heterogeneous group
of agents that have diverse structures e.g., tryptamines, substituted
phenylethylamines; and diverse basic mechanisms of action and
pharmacodynamic effects of “pure” psychedelic drugs e.g., LSD,
psilocybin compared to compounds with mixed effects e.g., dex-
tromethorphan. Despite some overlapping similarities, psychedelic
drugs cannot be easily categorized by their chemical structure,
mechanism of action, receptor binding profile, effects on mono-
amine uptake, behavioral pharmacology, therapeutic indication or
efficacy.
3. Scope of this chapter
The focus of this chapter is on the existing scientifically robust
human studies exploring the pharmacologic effects e including
safety and proof of concept studies –applicable to drug develop-
ment for a therapeutic purpose. An excellent recent review by
Nichols, includes details on mechanisms, neuropharmacology and
imaging studies in humans (Nichols, 2016).
In general, psychedelic agents have not been targets of phar-
maceutical development; hence the data are not typical of the usual
structured approach to research and development. While a large
and interesting data set based on self-report, religious ceremony,
ethnographic context and use exists, we have excluded all such
reports. We have included only studies that have been designed
prospectively with a clear objective and an attempt to randomize,
blind or control and systematically collect the observations. The
typical inclusion of only small numbers of highly selected subjects
severely limits generalizability.
Many of the studies cited in this chapter have concurrently
measured both psychoactive and physiologic effects of psyche-
delics. Classical hallucinogens acting via 5HT2A agonism in part can
exert dose-related physiologic effects such as pupil dilation,
elevated temperature, increases in heart rate, systolic and/or dia-
stolic blood pressure. These effects can potentially signal exposure
to drug and may be important safety signals. Some of the known
biologic effects of psychedelics may have implications for clinical
efficacy or safety after repeated dosing e.g., increases in pro-
opiomelanocortin peptides (corticotrophin and beta-endorphin),
prolactin, cortisol, growth hormone. While in general, controlled
clinical studies have not reported serious safety issues due to these
physiologic effects, some observed effects have been relatively
large e.g., increases in blood pressure. This poses a potentially
serious risk for some subjects and patients with untreated hyper-
tension or other disorders. Since the physiologic effects of 5HT2a
and 1a agonists and other neurotransmitter systems affected by
psychedelics are well known, this chapter will not discuss these
changes further.
Our initial intention was to describe as well as to compare the
pharmacodynamic and pharmacokinetic properties among classes
of psychedelics and within classes. This was impossible because of
lack of dose response data and lack of studies directly comparing
different psychedelic agents as well as the inconsistent use of
different measurement methods and scales.
Instead, we include selected “case studies” of several agents
with psychedelic properties for which more data exist e.g., LSD,
Please cite this article in press as: Sellers, E.M., et al., Studies with psychedelic drugs in human volunteers, Neuropharmacology (2017), https://
doi.org/10.1016/j.neuropharm.2017.11.029
3
psilocybin, DMT, salvinorin A, MDMA, ketamine, dextromethor-
phan and lorcaserin, a drug recently approved for appetite control/
obesity, and discuss how they illustrate challenges in human study
conduct. We have excluded deliriants (e.g., anticholinergics) and
cannabinoids because they do not meet the criteria proposed by
Hollister (1968). Our examples, illustrate the precautions and
methods that have been used to gather outcome data and phar-
macodynamic and safety data for psychedelics. We include com-
ments on scales and measures that have been used and highlight
their strengths and weaknesses.
Finally, in our conclusions, we summarize the challenges that
research with psychedelic substances must address if it is ever to
proceed on the development path to therapeutic agents and we
propose the types of human studies that are still needed.
4. Therapeutic studies
Studies with unapproved and strictly regulated psychedelic
substances have been conducted primarily in academic centers. All
proof of concept therapeutic trials have included supportive care
and psychotherapy. While well controlled trials have not been
completed in the past 15 years, preliminary therapeutic studies
have been conducted in obsessive-compulsive disorder, major
depression, cluster headache, alcohol and nicotine substance use
disorders, autism, post-traumatic stress disorder and the allevia-
tion of anxiety in life threatening disease (Carhart-Harris et al.,
2016) (Garcia-Romeu et al., 2014; Hendricks et al., 2015; Johnson
et al., 2014, 2017, 2012; MacLean et al., 2011). Pilot work has been
conducted with MDMA in post-traumatic stress disorder and
MDMA assisted psychotherapy for autism social impairment
(Danforth et al., 2016; Mithoefer et al., 2011, 2013; Yazar-Klosinski
and Mithoefer, 2017). Ibogaine has been studied for treatment of
opiate withdrawal and dependence (Koenig and Hilber, 2015;
Winkelman, 2014). Recent carefully conducted proof-of-concept
trials with psilocybin in anxiety and depressed mood in life
threatening cancer are illustrative of progress in human studies and
trial design and execution (Griffiths et al., 2016; Ross et al., 2016;
Sellers, 2017b).
More extensive research and data exists for ketamine which is
approved for sedation-anesthesia in many jurisdictions including
the US and Canada. Replicated studies include low dose ketamine in
treatment resistant depression (Berman et al., 2000; Xu et al., 2016).
Preliminary studies have also been conducted in obsessive
ecompulsive disorder, post-traumatic stress disorder, treatment
resistant generalized anxiety disorder and social anxiety disorder
(Feder et al., 2014; Glue et al., 2017; Rodriguez et al., 2013). A
controlled trial has been completed with ketamine assisted psy-
chotherapy for heroin dependence (Krupitsky et al., 2002, 2007;
Krupitsky and Grinenko, 1997). The s-isomer of ketamine has been
studied in adult treatment resistant depression (Singh et al., 2016).
5. Scientific constraints on human psychedelic agent research
Tables 1e3 summarize pharmacologic challenges, scientific
confounds and biases and design and measurement issues identi-
fied with human studies of psychedelics. [Table 1. Pharmacologic
Uncertainty: Mechanism of action, dose, kinetics and genetics;
Table 2. Study design confounds and biases in Psychedelic Trials;
Table 3. Choice of Study Dependent variables].
Probably no other class of agents has so many scientific and
practical issues to be considered prior to embarking on the search
for a potential therapeutic application. Several clinical research
laboratory groups have taken on the challenges and successfully
completed important pharmacology studies. Dr. Roland Griffiths
and colleagues at Johns Hopkins, have conducted high quality
4 Edward.M. Sellers et al. / Neuropharmacology xxx (2017) 1e19

Table 1
Pharmacologic Uncertainty: Mechanism of action, dose, kinetics and genetics.

Focus Comment

Mechanisms of action heterogeneous The basic mechanisms of action of psychedelics are unknown, complex and not identical involving many neurobiologic system
and complex elements. This makes drug disease interactions and drug-drug interactions very likely. Many different studies will be needed to
assess these risks.
Resetting the “default network” One integrated mechanism to explain the often sustained effects of psychedelics is that they reset the brains default network (see
Nichols, 2016). The possibility of resetting even part of the brain's default network would have wide scientific, medical, ethical and
social implications
Pharmacokinetic Incomplete information is available on metabolism with acute and chronic dosing of psychedelics. For example, the potential
impact of pharmacogenetic variations in drug metabolism in different populations is not known.
Genetics affecting pharmacodynamic Because most studies have been done in selected restricted populations little is known about how different disease phenotypes,
response genotypes and racial groups respond to psychedelics. At a basic level there is limited information on the effects of psychedelics on
gene and epigenetic expression and the possible persistence of such effects. Such factors are increasingly important in
neuropsychiatric and other medical disorders.

Table 2
Study design confounds and biases in psychedelic Trials.

Topic Comment

Difficulty blinding studies
Lack of acute and chronic dose response for
pharmacologic effects and safety
Lack of comparative studies of different psychedelic The range of mechanisms of action in available psychedelics is wide. Choice of test agent seems to have been largely
drugs
Subject/Patient numbers
Subject/patient bias and expectancy
Subject recruitment and selection
Study population
Subject pharmacologic qualification
Risk of psychiatric subject co-morbidity and risk
factors
Blinding trials where drugs have profound and obvious effects is difficult or impossible. Study monitors and
observers easily identify whether active drug has been given. Active “controls” and the use of placebo have been
attempted. Alternate approaches have included a “positive” control e.g., triazolam.
The goal of most trials to date has been to give a safe dose, not one chosen because it optimizes efficacy. A wide
variety of dose choices and dosing interval options exist a priori.
based on availability not an a priori preferred pharmacologic mechanism.
Prior experience with and interest in psychedelics is a common feature of participants in existing human studies.
Notwithstanding the complexity of such studies the low number of participants limits generalizability and suggests
actual acceptability of psychedelics may be quite low
Prior hallucinogen use is common in these study participants with likely high expectancy of a positive experience.
Study site previous research, focus and interest are easily known to participants. Consent forms are often explicit
about drugs and purpose. Randomized block and cross over designs do not help much in the presence of high
expectancy and intense study set and setting control.
Because of selection criteria studies screen relatively large numbers of subjects in order to find acceptable study
patients. Such a highly selected patient population limits generalizability of results and typically will mean the study
is conducted over a relatively long period. Such protracted study durations can be associated with secular trends and
staff changes. In therapeutic trials slow recruitment can reflect relatively low interest by patients or a small target
population
Study populations have not been representative of the general population composition. Often mainly Caucasian,
highly educated living in major urban centers with access to tertiary medical care.
In studies of the psychodynamic effects of hallucinogens, participants have been selected based on their history of
drug use. In none of the studies have subjects been tested before the main study to establish their reliability at
reporting the effects of the class of agents or specific agent being tested despite this being standard procedure in
other abuse potential assessment studies. Such pharmacologic qualification has proven to improve study power.
Incompletely explored since most patients with important comorbidity or risk factors are excluded. However, such
selection bias limits generalizability and poses potential substantial risks when use occurs outside of highly
controlled trials

Table 3
Choice of Study Dependent variables.

Topic Comment

Most drug effects are subjective and require accurate recall At low doses of psychedelics subjects seem able to respond but as doses increase task completion becomes
Dependent measures properties incompletely
characterized
Predictive validity or utility for measures dependent
variables not established
Non-pharmacologic information and psycho-social
support confound pharmacologic effects
more difficult probably due cognitive impairment and sensory inattention. Commonly used scales show large
variation suggesting either difficulty achieving or loss of instructional control
Commonly used scales can distinguish psychedelics from placebo and other drug classes but are poorly
characterized for their own measurement properties, specificity and sensitivity e.g., Hallucinogen Rating Scale
(HRS), States of Consciousness Questionnaire (SCQ). The subscales for these have descriptive titles attempting
to capture putative “mystical” or “transcendental” experiences. None of these sub-scales or instruments are
validated Patient Reported Outcome (PRO) measures for clinical trials nor are they surrogate markers of any
therapeutic outcome.
The above noted scales have shown sensitivity to hallucinogens, are able to distinguish psychedelics from non-
psychedelics and are sensitive cross culturally. When studied the scale items and totals show modest dose
response properties. Our analysis and examination of the dose response slopes and properties failed to show
subscale differences suggesting they are all sampling the same general subjective experience with different
words. The scale structures are fairly simple consisting of 4 or 5 point graded scaling items. Detailed factor
analysis for the most part has not been conducted nor have alternate scale versions with better measurement
properties been developed.
Given the high expectancy of subjects and the biases of study set and settings the contribution of the
pharmacologic agent may be small.

Please cite this article in press as: Sellers, E.M., et al., Studies with psychedelic drugs in human volunteers, Neuropharmacology (2017), https://
doi.org/10.1016/j.neuropharm.2017.11.029
 Edward.M. Sellers et al. / Neuropharmacology xxx (2017) 1e19
sustained research in this field and should be commended for
systematically addressing many of the constraints in the field to the
extent possible (Barrett et al., 2015; Carter et al., 2013; Garcia-
Romeu et al., 2014; Griffiths et al., 2008, 2016, 2011; Hendricks
et al., 2015; Johnson et al., 2008, 2014, 2016, 2017; Johnson and
Griffiths, 2013; ; Johnson et al., 2011, 2012; Lofwall et al., 2006;
MacLean et al., 2011, 2013; Maqueda et al., 2015; Maqueda et al.,
2016; Reissig et al., 2012).
6. The Safe conduct of human studies with psychedelics
Tables 4 and 5 summarize the principal safety concerns in hu-
man psychedelic research and the steps needed to mitigate risk.
[Table 4. Safety Concerns in Human Psychedelic Research; Table 5:
Safe Conduct of Human Psychedelic Research]. Tables 4 and 5 are
based on our experience and modified from and expanded upon
based on a useful review paper by Carter (Johnson et al., 2008).
7. Choice of measures of psychedelic drug effects
A wide range of scales and questionnaires have been developed
and used to assess the subjective effects of psychedelic drugs, with
varying degrees of characterization of their measurement proper-
ties. (Table 6). The scales are not separately referenced but de-
scriptions and details are readily available (Barrett et al., 2015;
Bowdle et al., 1998; Griffiths et al., 2008, 2011, 2006; Johnson
et al., 2011; Kometer et al., 2012; Reissig et al., 2012; Shram et al.,
2011a, 2011b; Studerus et al., 2010; Studerus et al., 2011). These
measurement approaches include Visual Analogue Scales (VAS),
typically 100 mm, Likert interval scale measures of positive and
negative drug effects as well as of class-specific pharmacologic ef-
fects (e.g. anxiety, agitation or feeling energized for stimulant like
drugs), and measures of drug class identification or similarity. Most
of measurement development has been done by two groups. The
approaches are similar but comparisons among the methods have
not been made (Kometer et al., 2012; Schmid et al., 2015; Studerus
et al., 2010)
Some of the measurements are old and have been demonstrated
to show poor sensitivity and specificity and high variance e.g., he
49-item ARCI or to be designed to have poor instructional control
e.g., 100 mm VAS scales (Haertzen, 1966; Haertzen et al., 1963;
Table 4
Safety concerns in human psychedelic research.
Safety Issue
Physiologic toxicity
Acute behavioral and psychologic distress including violence and self-harm, lasting
perceptual abnormalities (hallucinogen persisting perception disorder) including “flash-
backs”
Prolonged or precipitated psychosis
Overwhelming distress or “bad trip”
Impulsive behavior e.g., wanting to leave unit or harm oneself or others
Please cite this article in press as: Sellers, E.M., et al., Studies with psychedelic drugs in human volunteers, Neuropharmacology (2017), https://
doi.org/10.1016/j.neuropharm.2017.11.029
5
Martin et al., 1971; Shram et al., 2012).
Several scales have been used more commonly e.g., Halluci-
nogen Rating Scale (HRS), Mysticism Scale and the OAV related
scales (Table 7). They show sensitivity to hallucinogen effects, can
distinguish psychedelic from non-psychedelic drugs and are sen-
sitive cross culturally (Reissig et al., 2012). While writing this
chapter we examined some of these scales and their subscales and
confirm that they show modest dose response properties. A major
problem is that very few dose response studies have been con-
ducted upon which to assess the scale and sub-scale sensitivity. Our
preliminary analysis of the dose response slopes and maxima failed
to show many subscale differences. Potentially, these subscales may
be sampling the same general subjective experience but with
different words. Perhaps this lack of sensitivity is not surprising
since the scale structures include many items and each item rating
is simple, consisting of 4 or 5-point graded items. Detailed factor
analysis for the most part has not been conducted nor have alter-
nate scale versions with theoretically better measurement prop-
erties been tested.
One exception to scale characterization is the Altered States of
Consciousness rating scale based on data from 43 studies and
involving almost 600 subject exposures to psilocybin, ketamine and
MDMA (Studerus et al., 2010). This unique data base identified
improved scale structure and resolution into 11 factors. However,
scale characterization derived from large data bases often does not
enhance study data quality in typically small human pharmaco-
logic, proof of concept or mechanism studies. Even improved scale
properties cannot offset subject variation in small studies e.g., poor
instructional control, reporting bias and unreliability of set and
setting control.
While the difficulty of capturing the range of psychedelic effects
by subjective report is obvious, compared to other psychometric
measures e.g., Beck Depression Inventory most of the psychedelic
specific scales have not only many more items and but also have
been named with specialized jargon, to clusters and sub-scales
without demonstrating the unique contributing features of the
item group.
8. Selected case studies
The purpose of these cases and their discussion is to highlight
Prevention or Monitoring

Hypertension

Tachycardia and tachyarrhythmias

Hyperthermia

Impaired perception

Impaired proprioception

Intensive structured preparation of volunteers and session support by well-
trained monitors and staff

Careful screening to:
o Exclude volunteers with personal or family history of psychotic disorders
o Exclude volunteers with personal or family history of major mental
disorders e.g., depression, panic disorder, OCD.
o Exclude volunteers with personal or family history of certain personality
disorders e.g., avoidant personality, narcissistic personality disorder.

Establish rapport and trust between staff and volunteer before testing
session;

safe and secure facility that is familiar to volunteer;

careful volunteer preparation;

interpersonal support by at least two study monitors during study

Locked unit;

available security;

available emergency medical care
6 Edward.M. Sellers et al. / Neuropharmacology xxx (2017) 1e19

Table 5
Safe conduct of human psychedelic research.

Safety Issue Prevention or Monitoring

Volunteer
Healthy volunteers as assessed by structured medical history, physical examination biochemical and hematologic assessment, urinalysis, urine drug
selection scree and 12-lead ECG

Qualitative and quantitative time line follow back history of medication and recreational drug use.

Non hypertensive (<140/90 mm Hg)

Concurrent medication exclusions to include drugs with adverse effects related to altered perception and cognition e.g., tricyclic anti-depressant,
lithium; SSRIs; antipsychotics; MAO inhibitors e essentially all concurrent use of psychotropic medication and natural health products.

Alcohol use not permitted for 3 days prior to study session

Careful structured psychiatric screening e.g., SCID-5 or M.I.N.I. International Neuropsychiatric Interview (M.I.N.I. 6.0) by trained and certified in-
terviewers to exclude major psychiatric disorders e.g., schizophrenia, major depression, OCD.

Other exclusion based on purpose of study e e.g., if for adjunctive treatment of anxiety and depressive disorders, alcohol substance use disorder.

Moderate to severe disorders should be excluded
Study personnel
Immediately available emergency medical and psychiatric care

Great attention to “interpersonal atmosphere” achieved by study monitors

Monitors need pharmacologic, psychologic and medical understanding and experience with hallucinogen effects.

Personal experience with meditation, yoga or mindfulness and psychedelic drugs useful
Physical
Main issues are safety and setting conducive to the hallucinogen experience
environment
Setting “non-clinical” and “non-medical” e comfortable with control of lighting, temperature and colors

Locked and secure study facility with no potentially dangerous objects

Windows double or triple paned and locked

No extraneous sounds audible in the study area e.g., cell phones
Volunteer
Full and careful review and discussion of approved consent form with opportunity for open questions and discussion about concerns and
preparation procedures.

Volunteers should be systematically questioned with a standardized set of questions to ensure they fully understand the planned study.

The consent process should be videotaped.

Ideally preparation should consist of frequent introductory sessions e.g., 4 sessions (total 8 h) over a 1 month period with study monitors and
include spending orientation time in the study area. Preparatory interviews of volunteer should include learning of meaningful aspects of the
volunteers life e.g., spiritual beliefs.

Cautions to volunteers to avoid novelty or pre-session negative mood or other negative experience or stressors.

All staff familiar to volunteer

Full discussion and demonstration of procedures and tests
Session Conduct
Physician and emergency services available

Volunteer always closely accompanied when ambulating

Two monitors male and female or the same sex/gender as volunteer have been proposed along with the suggestion to avoid two of the opposite sex/
gender

Reassurance and guidance

Washrooms unlockable

Physically restrain and prevent volunteers from leaving facility

Dissociative and disconnected experiences handled with inter-personal grounding and touching. During an intense experience volunteers may not
respond to verbal stimuli.

In severe or protracted experiences that cannot be handled with support, medications e.g., rapid acting benzodiazepines such as diazepam or
antipsychotic medication may need to be administered

Moving a volunteer from the protected and reassuring setting to an unfamiliar one with staff not accustomed to managing hallucinogenic reactions
may exacerbate the problem e.g., Emergency Room
Post-session The impact of the experience can be very profound hence several follow up visits over a month's period with questioning of the participant and their
follow-up friends or family concerning behavior is critical. Many studies include a debriefing where subjects are asked about the meaningfulness of the
experience and how it has affected their behavior.

not only pharmacodynamic, pharmacokinetic and other features of
psychedelics with nominally different mechanisms of action but
also highlight the recurring design and analysis scientific chal-
lenges, biases, and confounds of such studies as summarized in
Tables 1e3 Since proper dose response studies and direct com-
parisons are so rare, most comparative pharmacologic conclusions
are tentative.
8.1. Lysergic acid diethylamide (LSD)
Despite being the best known and most described “psychedelic”
LSD has had few systematic human studies and none that have
incorporated blinded, controlled dose response design or involved
direct head to head comparisons to other psychedelics (Dolder
et al., 2015; Gasser et al., 2014; Kupferschmidt, 2014).
8.1.1. Pharmacokinetics
One study characterized the pharmacokinetic profile,
pharmacokinetic-pharmacodynamic relationship, and urine re-
covery of LSD and its main metabolite after administration of a
single oral dose of LSD (200 mg) in 8 male and 8 female healthy
subjects with moderate experience with hallucinogenic drugs
(mean age 28.6 years ± 6.2 (range 25e51) (Dolder et al., 2015)).
Plasma LSD concentrations were quantifiable (>0.1 ng/ml) in all
the subjects up to 12 h after administration. Maximal concentra-
tions of LSD (mean ± SD): 4.5 ± 1.4 ng/ml were reached (median,
range) 1.5 (0.5e4) hours after administration. Concentrations then
decreased following first-order kinetics with a half-life of
3.6 ± 0.9 h up to 12 h and slower elimination thereafter with a
terminal half-life of 8.9 ± 5.9 h. This illustrates large variation in
biotransformation. Such variation has typically been ignored in
therapeutic studies with psychedelics. The importance for LSD is
unknown.
One percent of the orally administered LSD was eliminated in
urine as LSD, and 13% was eliminated as 2-oxo-3-hydroxy-LSD
within 24 h. No sex differences were observed in the pharmaco-
kinetic profiles of lysergic acid diethylamide however, the sample
size was small consisting of younger individuals of unspecified
racial background.
8.1.2. Pharmacodynamics
Measured end-points included heart rate, arterial pressure,

Please cite this article in press as: Sellers, E.M., et al., Studies with psychedelic drugs in human volunteers, Neuropharmacology (2017), https://
doi.org/10.1016/j.neuropharm.2017.11.029
 Edward.M. Sellers et al. / Neuropharmacology xxx (2017) 1e19 7

Table 6
Pharmacodynamic Measures Used in Human Studies of Psychedelic drugs.

Type or Name Description and Examples

Physiologic Measures
Blood pressure and heart rate
Psychomotor Performance and Attention

Circular lights;

Balance;

Manual tracking task

Digit Symbol Substitution test (DSST)
Visual Analog Scales (VAS)
Typically 100 mm lines ranging from “not at all” to “most intense I have ever had”. Examples of VAS dimensions include floating,
spaced out, vision clear, liking, disliking, bad effects, any effects, good effects, high To decrease measurement variance, bipolar
scales can be used anchored by a neutral point in the middle. Such scales are appropriate for measures with a dichotomized
range e.g., liking-disliking.
Profile of Mood States (POMS)
72 items with subscales such as vigor and confusion have been employed
Bowdle Rating Scale
Visual analog (VAS) rating of 13 symptoms. Originally used for studies of intravenous ketamine
Addiction Research Inventory ARCIe Short Form
49 Item version. Questions are to be answered “yes” or “no”. Thetre are 5 subscales

LSD,

MBG,

BG,

PCAG,

Amphetamine
Monitor Rating questionnaire
Observers rate 16 dimensions of behavior or mood on a 5 point scale
Subjective Effects Questionnaire
Subject rates 36 Items on a 100 mm line e.g., Do you feel any effect; do you feel light headed etc. “No”, “not at all” to “yes very
much”.
Hallucinogen Rating Scale (HRS)
99 item questionnaire designed originally to show sensitivity to DMT.

Intensity,

Somaesthesis

Affect Perception

Cognition

Volition

Intensity
Mysticism Scale
32 item paper questionnaire to assess naturally occurring mystical experiences. Subscales:

Interpretation;

Introvertive;

Extrovertive;

Total
States of Consciousness Questionnaire (SCQ)
100 item questionnaire rated on a 5 point scale 0 ¼ none to 5 ¼ extreme. 43 items of this questionnaire also comprise a version of
the Pahnke e Richards Mystical experience items sensitive to psilocybin. The 43 items provide scores for 7 domains. The
remainder 57 items are distractors

Internal Unity

External Unity

Sense of Sacredness

Intuitive knowledge

Transcendence space

Deeply felt positive mood

Ineffability

Total
Altered states of Consciousness (5D-ASC) Visual analog self-rating scale of 84 items assesses 5 primary dimensions and one global dimension of ASC

Oceanic Boundlessness (OB)

Anxious Ego Dissolution (AED)

Visionary Restructuralization (VR)

Auditory Alterations (AA)

Reduction of Vigilance (RV)
Pharmacologic Class Questionnaire
Asks subject about the similarity of the proximate drug experience to their previous experience. Subject are asked only about
similarity to drugs they have actually taken in the past.
Cognitive Performance Measures

DSST;

Divided Attention;

Working Memory;

Episodic Memory;

Free Recall;

Word Recognition;

Metacognition
Persistent Effects Questionnaire
143 item questionnaire using 6 point scale assessing persistent changes in mood, attitude, behavior and spiritual experience. 3
items ask about the extent to which the experience was meaningful and important. 140 items rated on 6 point scale. Subscales
(continued on next page)

Please cite this article in press as: Sellers, E.M., et al., Studies with psychedelic drugs in human volunteers, Neuropharmacology (2017), https://
doi.org/10.1016/j.neuropharm.2017.11.029
8 Edward.M. Sellers et al. / Neuropharmacology xxx (2017) 1e19

Table 6 (continued )

Type or Name Description and Examples

Attitudes about life

Attitudes about self

Mood Changes

Relationships

Behavioral Changes

Spirituality
Assessment of Meanfulness
Variety of ways to assess how meaningful the experience was. One version asks 3 questions that are rated on a scale of 1e8
Adjective Mood Rating Scale (AMRS)
Self-rating scale to assess mood states and conditions. List of 60 adjectives rated by subjects as to how well the terms describe
how they feel at the moment. There are 15 mood states and conditions included
Long-term evaluations
Ratings of acute drug experience in retrospect

Changes in values and attitudes

Changes in drug consumption

Spontaneously occurring altered states of consciousness before and after experience and flashbacks

Negative changes in psychological wellbeing and/or mental functioning

Table 7
Practical and Regulatory obstacles to drug approval of psychedelic agents.

Obstacle Comment

International and national restrictions on possession and use Because of their profound acute behavioral toxicity all classical hallucinogens are strictly
controlled under the Convention on Psychotropic Drugs (1971) and the Controlled Substances
Act (USA). This has undoubtedly inhibited research on these types of compounds.
Lack of intellectual property protection Composition of matter protection is likely to only apply to new analogs of existing psychedelic
drugs or some of their isomers. There are hundreds of structures that have been synthesized but
these are also largely in the public domain. Use patents for a highly restricted unmet medical
need may be feasible in some cases but would likely only have intellectual property weight in
the United States
Purity of material often not known Plant derived material and extracts qualitatively characterized but quantities and contributions
of “minor” constituents unknown.
GMP manufacturing not readily available Several academic laboratories have developed GMP synthesis capacity
Risks to the pharmaceutical industry Lack of intellectual property protection and the perceived high risk of behavioral toxicity
Risks for Regulatory Authority Both the FDA and DEA would likely perceive marketing of a psychedelic drug as a potentially
serious public health risk
Risks for public health authorities and law enforcement Drug abuse especially of a prescription drugs, is widely recognized by health and law
enforcement professionals as a serious problem. Great concern about wider availability of a
psychedelic would be likely
Historical perception about research with these agents and the passionate Use of and research with hallucinogens engenders a wide range of views between puzzlement
advocacy of some groups about the role of hallucinogens and opposition hence lack of enthusiasm for therapeutic use may occur
Mitigating liability The potential for profound behavioral toxicity occurring outside of carefully supervised settings
and controlled drug dispensing would carry considerable product liability
Requirement for site license to conduct studies As internationally restricted substances special authorization is required to conduct studies
with most psychedelic agents and even if approved would require a Schedule II license.
Extent and range of data required for an NDA While some accelerated pathways to approval may be possible the wide range of required acute
and chronic safety data and comparative clinical trials will not be materially less for
psychedelics seeking market approval.
Likelihood with an approved medical indication a psychedelic will be C-II While some examples of Schedule 1 drugs being placed in Schedule III e.g., Marinol®, GHB
of the Controlled Substances Act. Xyrem® such bifurcated scheduling is rare. Barring any political or other intervention a C-I
compound with and approved medical use will be placed in C-II with its attendant restrictions
on prescribing and record keeping and annual quotas and security
Approvable medical indication is likely to be for an unmet medical need Some of the therapeutic areas explored with psychedelics e.g., depression may not qualify.
There may be subsets of refractory patients for whom an approved use might exist e.g., PTSD or
depression with suicidal ideation
Maximizing therapeutic effectiveness not just efficacy Drugs are approved based on demonstrated efficacy on well econtrolled and conducted Phase
III studies. However, once on the market many factors impair this efficacy and result in much
lower effectiveness in actual practice. Current psychotropic agents are not used optimally nor
are the adjunctive or alternate therapies e.g., psychotherapy, CBT etc.
Cost to meet regulatory requirements for an accepted New Drug Current estimates suggest that it costs $2.6B to obtain approval for a new drug
Application
Small pool of qualified investigators, trained staff and sites to work with As Table 6 outlines, the infra-structure and staff training required for conducting human studies
psychedelics with psychedelic is extensive and not typical of most treatment contexts. Certain specialty areas
and specialty facilities could provide such treatment but costs are likely to be very high
Healthcare delivery and costs Many patients with conditions that might be treated with psychedelic drugs have neither the
financial resources nor access to treatments that would be needed. Only expansion of
healthcare availability and reductions in costs can address this challenge.
Approval would be accompanied by a comprehensive Risk Evaluation and In addition, to the requirements of the CSA Schedule II or III, a REMS would be likely required
Mitigation strategy with an approved psychedelic. This would include patient registries, site training and
certification, restricted drug release, proscribed management and education programs. GHB
Xyrem® provides one model.

Please cite this article in press as: Sellers, E.M., et al., Studies with psychedelic drugs in human volunteers, Neuropharmacology (2017), https://
doi.org/10.1016/j.neuropharm.2017.11.029
 Edward.M. Sellers et al. / Neuropharmacology xxx (2017) 1e19
body temperature, pupil size, “any drug effect”, “good drug effect”
and “bad drug effect”. This study included partially validated
measures of altered perception or other experiences e.g., 5 Di-
mensions of Altered States of Consciousness (5D-ASC), Visual
Analog scales, Adjective Mood Rating Scale (AMRS), Addiction
Research Center Inventory. These were reported in a separate paper
for the same study with detailed supplemental material (Schmid
et al., 2015).
Outcome measures included psychometric scales; investigator
ratings; pre-pulse inhibition (PPI) of the acoustic startle response;
and autonomic, endocrine, and adverse effects. Administration of
LSD to healthy subjects produced pronounced alterations in waking
consciousness that lasted 12 h. The predominant effects induced by
LSD included visual hallucinations, audiovisual synesthesia, and
positively experienced derealization and depersonalization phe-
nomena. Subjective well-being, happiness, closeness to others,
openness, and trust were increased by LSD. Compared with pla-
cebo, LSD decreased pre-pulse inhibition (PPI). LSD significantly
increased blood pressure, heart rate, body temperature, pupil size,
plasma cortisol, prolactin, oxytocin, and epinephrine. Adverse ef-
fects produced by LSD completely subsided within 72 h. Increases
in oxytocin have been found to on their own to increase attach-
ment, evaluating and responding to social stimuli, mediating social
interactions, and forming social memories (Cochran et al., 2013).
No severe acute adverse effects were observed. This indicates
that LSD can be administered safely in a controlled setting with
careful dose selection, subject supervision and preparation and
experienced staff.
In addition to marked hallucinogenic effects, LSD was reported
to promote enhanced sociability and connection or a “methyl-
enedioxymethamphetamine-like empathogenic mood” effect. The
authors suggest this effect may explain the potential utility of LSD
and psychedelics as adjuncts to psychotherapy.
The acute subjective and sympathomimetic responses to LSD
lasted up to 12 h, were closely associated with the concentrations in
plasma over time and exhibited no acute tolerance using hysteresis
plots of sequential concentrations versus time of sample (Sellers
et al., 1972a, 1972b). Many sedating psychotropic drugs, ethanol
and opiates, do show acute tolerance with the consequence that
drug effects decrease much faster than plasma concentrations and
plasma drug concentrations do not correlate very closely with
pharmacodynamic actions. Other forms of tolerance such as
learned tolerance and tolerance during chronic dosing do not
appear to have been systematically studied for most psychedelic
drugs and could be important clinically (Carroll, 1990; Holland and
Ferner, 2017; Kalant, 1998; Le and Kalant, 1990; Parrott, 2005;
Suwaki et al., 2001). Since LSD has a terminal half-life that ex-
ceeds the duration of action this could reflect plasma or brain
concentration, that were too low for effect or that in fact there was
development of tolerance after the initial effects.
8.2. Psilocybin
Many descriptive and partially controlled studies have been
conducted with psilocybin. (Bogenschutz et al., 2015; Breckenridge
and Grobbee, 2016; Carhart-Harris et al., 2011, 2012a, 2012b, 2013,
2016; En.wikipedia.org, 2017; Garcia-Romeu et al., 2014; Geyer,
2015; Griffiths et al., 2008, 2016, 2011; Hendricks et al., 2015;
Johnson et al., 2014, 2017; Kometer et al., 2015; MacLean et al.,
2011; McCorvy et al., 2016; Nutt, 2016; Passie et al., 2002; Roseman
et al., 2014; Ross et al., 2016; Sellers, 2017b; Spiegel, 2016; Studerus
et al., 2012; Turton et al., 2014; Tyls et al., 2014). In this chapter we
summarize only three aspects of this work. First, pharmacokinetics,
second, several well controlled experimental human studies that
included dose response assessments of effects and third, two recent
Please cite this article in press as: Sellers, E.M., et al., Studies with psychedelic drugs in human volunteers, Neuropharmacology (2017), https://
doi.org/10.1016/j.neuropharm.2017.11.029
9
well-done therapeutic clinical trials. We have selected these trials
because they are thoughtfully designed, carefully conducted and
described and illustrate many of the challenges of human psyche-
delic research.
8.2.1. Psilocybin pharmacokinetics
Psilocybin undergoes hepatic first pass biotransformation with
conversion to psilocin, the pharmacologically active metabolite.
Pharmacokinetic data exist for psilocybin and psilocin (Hasler et al.,
1997; Passie et al., 2002). After oral administration, psilocin reaches
peak concentration in about 100 min ( ±2.8 SD) and has a half-life
of 160 min ( ±63 SD). Systemic bioavailability is 52% (Sellers,
2017b).
8.2.2. Pharmacodynamics
A clear picture of the effects of psilocybin in humans emerges
from a series of well-done and comprehensive studies (Griffiths
et al., 2008, 2011, 2006; Johnson et al., 2012; Studerus et al., 2011,
2012). Earlier work in 36 hallucinogen naïve volunteers given
high doses of psilocybin (30mg/70 kg) in a supportive and highly
controlled environment showed that psilocybin was associated
with mystical experiences and sometimes substantial fear, lasting
up to 6 h (Griffiths et al., 2006). The mystical experiences were
reported to have sustained personal meaning and spiritual signif-
icance that were reflected in positive changes in attitudes, moods
and behaviors. A subsequent, double blind controlled study in 18
adults (17 hallucinogen naïve) examined a range of lower
ascending and descending doses between 0 and 30 mg/70 kg.
Stringent selection criteria were used: 279 individuals were
screened over the phone and 31 in person. Although hallucinogen
naïve, the selected group were highly educated (94% had a college
degree), most were employed or retired and all indicated an in-
terest in or involvement in spiritual or meditation practices. Psi-
locybin produced acute perceptual and subjective effects including,
at 20 and/or 30 mg/70 kg, extreme anxiety/fear (39% of volunteers)
and/or mystical-type experience (72% of volunteers). One month
after sessions at the two highest doses, volunteers rated the psi-
locybin experience as having substantial personal and spiritual
significance, with sustained positive changes in attitudes, mood,
and behavior. The ascending dose sequence showed greater posi-
tive effects. At 14 months, ratings were undiminished and were
consistent with changes rated by community observers. Both the
acute and persisting effects of psilocybin were generally a mono-
tonically increasing function of dose, with the lowest dose showing
significant effects (Griffiths et al., 2006). An interesting adverse
effect, seen in this study was a dose related, delayed onset of
transient headaches of mild to moderate severity that lasted up to a
day (Johnson et al., 2012). The exact mechanism of the headaches
occurring after the psychedelic effects is unknown although
disruption of normal 5HT activity in various brain nuclei or in
cranial blood vessels could play a role.
The largest analysis of psilocybin pharmacodynamics comes
from an analysis of 110 healthy subjects who received up to 4 doses
of psilocybin (45e315 mg/kg) (Studerus et al., 2011). As expected
dose related profound changes in mood, perception, thought and
“self-experience” occurred. The experiences were largely described
as pleasurable and enriching. Acute adverse effects e.g., dysphoria,
anxiety, panic were uncommon, occurred at the highest doses and
were managed conservatively with support. No long term adverse
sequelae were reported. As with other subject pools, these partic-
ipants were well screened and prepared, healthy, well-prepared
and high functioning volunteers (Studerus et al., 2011).
A subsequent analysis of 261 volunteers who had received a
total of 409 psilocybin exposures revealed that after dose, as a
predictor, that a pleasant mystical experience was associated with a
10 Edward.M. Sellers et al. / Neuropharmacology xxx (2017) 1e19
baseline low emotional excitable state, a high score on “Absorption”
and having had few psychologic problems in the previous week.
Conversely, high emotional excitability, younger age and being
confined in a PET machine was most associated with an unpleasant
or anxious reaction (Studerus et al., 2012).
8.2.3. Phase II proof of concept studies
Two randomized “blinded, controlled” clinical trials (the Johns
Hopkins University trial (JHU) and New York University trial (NYU))
reported long-term reductions in anxious and depressed mood,
existential distress and improved quality of life after single oral
doses of psilocybin in patients with terminal illnesses (Griffiths
et al., 2016; Ross et al., 2016). The large and sustained effects on
mood were very impressive because evidence of efficacy of anti-
depressants and other medications in life threatening diseases is
limited (Spiegel, 2016). Antidepressant have not been very effective
in such patients (Ostuzzi et al., 2015). However, group supportive
psychotherapy and other forms of psychotherapy can help such
patients feel more in control, reduce depressive symptoms and
hopelessness, improve social functioning and quality of life and
result in longer survival (Spiegel, 2016). Both trials provided
extensive, concurrent psychotherapy and supportive care by highly
trained experienced staff and this adjunctive care was likely central
to the benefit as well as the safety data reported (see Table 1
(Sellers, 2017b)).
The JHU and NYU studies have many strengths including mul-
tiple subjective end points and assessments by the patient, family,
community observers and clinicians (Sellers, 2017b). These trials
illustrate the challenges shared by all trials with psychedelics.
These included: the relatively small number of participants; highly
selected populations (e.g., urban, Caucasian, high levels of educa-
tion, prior use of hallucinogens and cannabis), highly structured
study settings, intensive monitoring supportive care and psycho-
therapy, and a protracted trial duration (Sellers, 2017b) [see also
Table 3]. Despite careful trial conduct, neither of these trials were
randomized (a within patient cross over design was used) and in-
ternational regulatory and pharmaceutical clinical trial standards
including independent audit and monitoring and data entry and
verification were not used.
Efforts were made in both trials to utilize a double-blind,
controlled design. In one study, the comparator or “placebo” was
a low dose of psilocybin and the other study used niacin. Blinding of
trials where a drug has obvious effects is difficult. While both
studies used within subject crossover designs, this approach con-
founds study population bias, patient expectancy, the impact of
study set and setting, the interaction of the drug's effects with
supportive care and counselling.
In common with other studies with psychedelic drugs, these
trials demonstrate that in carefully controlled settings psilocybin
can be administered safely, from a cardiovascular and neurologic
perspective. However, from a therapeutic perspective unanswered
questions include the minimal effective and maximum tolerated
doses and optimal doses. Single dose studies, clearly do not address
repeat dose effects, carry-over and long-term safety in settings of
actual practice. The impact of a more clinically and genetically
diverse subject population on pharmacokinetics and effects re-
mains an unknown.
8.3. N, N-Dimethyltryptamine (DMT)
DMT is another plant derived hallucinogen found in Prestonia
amazonica and in trace amounts in human brain, blood and urine.
Normally it is inactive if taken orally on its own because of meta-
bolism by monoamine oxidase in the gastrointestinal tract and liver
but when combined with an MAO inhibitor, as occurs with the
Please cite this article in press as: Sellers, E.M., et al., Studies with psychedelic drugs in human volunteers, Neuropharmacology (2017), https://
doi.org/10.1016/j.neuropharm.2017.11.029
South American plant solution ayahuasca an admixture of psy-
chotrica viridis (the DMT source) and the vine Banisteriopsis caapi
(the MAO source), it causes intense visual hallucinations and
euphoria. Pure DMT has also been prepared for intravenous
administration (Strassman, 1996; Strassman et al., 1994).
8.3.1. Pharmacokinetics and pharmacodynamics
An intravenous study evaluating pharmacokinetic and dynamic
effects of DMT has been conducted (N ¼ 12; 11 males; 1 female;
mean ± SEM 41.5 ± 1.5 years). The study report provides a detailed
account of the issues that bear on conduct of studies with DMT and
other psychedelic agents. The execution of detailed comprehensive
pre-study medical, biochemical and psychiatric assessment
included a structured diagnostic interview, the SCID-R. A strong
feature of this study was the use of a non-blinded screening
administration of DMT at 2 doses to assess tolerability, to make
subjects familiar with the drug effects and procedures and to
introduce the study staff. However, this initial screening adminis-
tration of DMT did not seem to have been used to assess subject
reporting reliability, a potential major source of study variability
(Busto et al., 1999). The study population were all high academic
achiever (professionals or students in a professional program
except one subject), prior heavy users of at least one psychedelic
(6e100 times), marijuana (10e1000s of times), cocaine/amphet-
amines (0e100), MDMA (0e100), had a high incidence of prior
depression and first-degree family history of substance abuse and
psychiatric illness; and had a cumulative total of 18 divorces among
them!
The study conduct was set up as appropriate for an intravenous
administration study. However, in a rare acknowledgement of
practical issues that can arise it was noted that blood could not be
obtained from one female subject because of poor venous access;
pupil diameter measurements were incomplete because some
subjects did not want to open their eyes during the study; poor
quality temperature data collection occurred in two subjects; the
refusal by one subject to accept the rectal temperature probe
(which parenthetically seems unnecessarily, even inappropriately
invasive for a study of a perception and mood altering substance).
One subject had to be withdrawn from the study because of the
occurrence of major depression.
The study was a double blind randomized and placebo
controlled design at doses of 0.05, 0.1, 0.2 and 0.4 mg/kg of DMT.
Intravenous DMT was fully hallucinogenic at 0.2 and 0.4 mg/kg
with peak effect occurring at 2 min and abating by 30 min. DMT
blood concentrations patterned the pharmacologic effects. The
time course of hormones and peptides, heart rate and blood pres-
sure also paralleled the DMT concentrations. Peak DMT plasma
concentrations varied widely at 0.4 mg/kg and were between 32
and 204 ng/ml.
All subjects, except one, reported visual hallucinations after the
0.2 and 0.4 mg/kg infusions. Auditory hallucinations were experi-
enced by most subjects. Somatic sensations of intense rush, often
with a feeling of dissociation, were associated with transient
anxious or fearful emotional reactions (Strassman et al., 1994).
The paper provided details on the development of the Halluci-
nogen Rating Scale (HRS) (Strassman et al., 1994). In summary, the
scale was composed by using reports from subjects, grouping by
clinically similar clusters, including general experiences related to
hallucinogens and those thought to be unique to DMT and principal
components analysis. Questions were 5-point scales 0e4, “not at all
to extremely”, for 126 items. The verbatim accounts of the effects
reported by subjects seem more effective than the scale measures
at capturing the qualitative effects of DMT and underscoring some
apparent differences from other psychedelics. This paper contains a
useful brief history of the attempts to develop measures and scales
 Edward.M. Sellers et al. / Neuropharmacology xxx (2017) 1e19
to quantitate hallucinogen effects. The post-hoc Principal Factors
Analysis identified 76 questions within 6 clinical clusters that
demonstrated consistent dose response patterns. However, the
similar slopes of the factors across doses suggests that no scale has
particularly strong discriminative properties.
The effects of DMT were much shorter in duration than those of
LSD. Clearly, as with other psychedelics, such studies can be done
safely, at least with acute dosing. However, the subject character-
istics underscore the lack of generalizability of any of the obser-
vations in this study to a therapeutic context.
Another study with DMT in 6 subjects (3 males; 3 females) with
a DMT extract by oral and smoked route yielded similar effect
patterns and confirmed the lack of effects orally but full effects by
smoking the product. Both the HRS and the States of Consciousness
Questionnaire (SCQ) subscales were all sensitive to DMT effects
after smoking. No plasma concentrations were measured; however,
DMT exposure after smoking was confirmed by presence of un-
changed DMT in the urine (Riba et al., 2015).
8.4. Salvinorin A
Salvia divinorum, the plant source of salvinorin A has become
popular as a recreational drug (Vortherms and Roth, 2006). Salvi-
norin A is structurally distinct from other psychotropic drugs and
differs in mechanism of action in that it acts primarily as a highly
specific and selective kappa opioid agonist (Roth et al., 2002). The
hallucinogenic effects of salvinorin A are reported to be more
intense than those of other psychedelics (Cruz et al., 2017)
Salvinorin in its leaf form can be chewed or used for buccal
absorption or by drinking an infusion of fresh leaves of S. divino-
rum. It has been used for medicinal, spiritual other purposes (Cruz
et al., 2017; Johnson et al., 2011). The effects of the agent include
visual and auditory effects, perceptual modification, dizziness and
uncontrolled laughter (Cruz et al., 2017). Users claim positive after-
effects on insight and improved mood (Baggott et al., 2010). A wide
range of potential therapeutic uses including anti-nociception,
antidepressant, anti-addictive, neuroprotection, antidiarrheal,
anti-inflammatory immune activator effects have been proposed
(Cruz et al., 2017).
8.4.1. Pharmacokinetics - animals
The dried leaves of the salvia divinorum plant can be smoked
and produce a rapid onset of visual hallucinations, behavioral and
motor function impairment which last only a few minutes (Hooker
et al., 2008). PET studies after intravenous administration, to ba-
boons (N ¼ 6) of C11 radiolabeled salvinorin A, reached peak brain
concentrations within 40 s and the compound was eliminated with
a half-life of 8 min (Hooker et al., 2008). This extraordinarily rapid
rate of brain entry and removal suggests active transport systems
are playing a role in crossing the blood brain barrier. Naloxone had
no effect on the salvinorin kinetics or dynamics. The concentrations
of salvinorin in the brain did not correlate with kappa receptor
distribution, suggesting considerable nonspecific and non-selective
localization. Higher concentrations of salvinorin in cerebellum and
cortex would be consistent with its behavioral and hallucinogenic
effects.
8.4.2. Pharmacodynamics e human
Extracted and purified salvinorin A inhalation at 16 distinct
doses intermixed with 4 placebo sessions, has been studied in 4
healthy subjects (2 males and 2 females; age range 23e35)
(Johnson et al., 2011). All subjects had prior experience with sal-
vinorin (range 2e40 uses in past 5 years), were carefully screened
and expressed an interest in spirituality and/or altered states of
consciousness. Dosing ranged from 0.375 mg/Kg to 21 mg/Kg and the
Please cite this article in press as: Sellers, E.M., et al., Studies with psychedelic drugs in human volunteers, Neuropharmacology (2017), https://
doi.org/10.1016/j.neuropharm.2017.11.029
11
study was conducted over an 8e14-week period. Subject prepara-
tion, study setting and procedure were carefully standardized and
supportive of the expected drug effects.
In addition to blood pressure and heart rate, tremor was
measured.
Strength of drug effect and Likert scale evaluations of drug
liking, drug disliking, good effect, bad effects were recorded on a 5-
point scale. In addition, the Hallucinogen Rating Scale (HRS 99
items) and its 6 sub-scales, and the Mysticism Scale (MS 32 item 9-
point scales for each question) were completed at 1.0 h after
inhaled drug was administered.
Onset of effects was very rapid (<2 min) and lasted only 20 min,
consistent with the previous data from baboons. At high doses (>15
mg/kg), several subjects were unresponsive and unable to rate peak
effects. In general, drug strength and peak subjective effects
increased with dose with insignificant effect on physiologic
measures.
Because of the limited number of subjects, the HRS Subscales
and the MS showed few significant differences across doses. At
best, modest dose response patterns were seen. The HRS-Intensity
scale showed significant changes at > 4.5ug/kg but appeared to
plateau at the same level. The HRS eVolition Scale showed no
significant effects. The HRS eAffect was only significantly altered at
18 mg/kg, the HRS eCognition at >15 mg/kg and the HRS Perception
at > 18 mg/kg. These data suggest generally poor sensitivity for the
subscales, ceiling effects and that the HRS Intensity is very similar
and highly cross correlated with “drug strength”.
An expanded subject pool (N ¼ 8; 5 males, 3 females) of the data
collected in the above study reported on the dissociative, halluci-
nogenic and memory effects of salvinorin A (MacLean et al., 2013).
Added measures in this report included: End of session rating of
liking/good effect; the HRS and the APZ; Mysticism Scale, SOCQ;
Perception Scale; ARCI; STAI; Quantitative Pharmacologic Class
Questionnaire (QPCQ); Word Recall and Recognition; Open Ended
Narratives Session Day Experience. [see Table 6 for abbreviations
and scale description].
As in previous data, an orderly dose response pattern was
evident for drug strength across the dose range, as reported by
subjects and monitors although generally not until doses were
greater than 6 mg/kg. At doses >18 mg/kg unresponsiveness was
common. Some of the HRS and PCSQ data suggested some overlap
with 5HT2A agonist hallucinogens but salvinorin produced dose
related dissociative effects and impairments in recall/recognition
memory. The subjects reported salvinorin A effects were qualita-
tively different from other drugs.
The most robust effects were on drug strength and the HRS
Intensity and Drug Liking subscales. Since subjects were previous
users of salvinorin, the latter result is not surprising. On other scales
of the HRS, the APZ and SOCQ changes were inconsistent and when
they occurred it was only relatively high doses e.g., >12 mg/kg. The P
Scale showed changes in the total score and detachment at doses of
4.5 mg/kg suggesting a confound with drug strength. The ARCI failed
to detect any changes.
On the SOCQ all scales except positive mood showed a threshold
for significant changes at 12 mg/kg suggesting the subscales are
highly correlated.
8.5. Ketamine
Ketamine, a well-characterized NMDA antagonist dissociative
agent placed in Schedule III of the Controlled Substances Act and
approved as a sedative-anesthetic, has been a logical choice for
investigators to study as an adjunct for treatment of various dis-
orders e.g., depression, anxiety, PTSD (Feder et al., 2014; Glue et al.,
2017; Schak et al., 2016; Vande Voort et al., 2016). Ketamine can be
12 Edward.M. Sellers et al. / Neuropharmacology xxx (2017) 1e19
administered intravenously, orally and sublingually. Parentheti-
cally, it also has a taste that requires the use of strong masking
agents when administered orally. In addition, it has been used as a
“positive control” in human abuse potential studies where the new
test agent is suspected to have properties that alter perception or
could cause hallucinations (Shram et al., 2011a, 2011b). Ketamine
studies in mood and anxiety disorders resistant to other treatments
illustrate again the challenges of working with psychedelic agents.
A recent Consensus Statement identifies the “small sample sizes,
lack of longer-term efficacy data and limited data on safety and
behavioral toxicity” as short-comings in research to date (Sanacora
et al., 2017). This statement also points to issues in patient selection,
training of staff and preparation of the patients, need for careful and
in-depth assessment and ruling out of concurrent contraindications
or clinical risks including hypertension, selection and control of
treatment setting and safety monitoring. Because ketamine is an
approved drug, strict adherence to practice guidelines is required to
discourage “off-label” use. The extent of off-label, non-evidence
based use is of concern with ketamine since it has the potential for
behavioral toxicity and lacks long-term safety data (Wilkinson and
Sanacora, 2017; Wilkinson et al., 2017).
8.5.1. Pharmacokinetics
The pharmacokinetics of ketamine and their implications for
clinical effects are likely complex because ketamine has two ste-
reoisomers: S (þ) and R ()-ketamine with differing specificity and
selectivity for NMDA receptors (S > R) and the principal metabolite
(norketamine), though less specific and selective than the parent
drug, has about 40% of the activity (Niesters and Dahan, 2012).
Various administration modes can be used: oral, nasal, sublingual,
subcutaneous, rectal, transcutaneous and intravenous. Non-
intravenous bioavailability is variable (25e40%). After intravenous
administration ketamine, the distributional half-life is 15 min with
a terminal half-life of 2e3 h. Following an intravenous infusion,
women have about 20% higher elimination of both S-ketamine and
S-norketamine, leading to higher drug concentrations in men at
equivalent doses compared to women. This possibly explains the
greater loss of memory and verbal recall observed in men than in
women after a similar ketamine treatment dose. Alternately, there
may be sex differences in sensitivity. Ketamine is predominantly
metabolized in the liver, through the CYP3A4 and CYP2B6 cyto-
chrome P450 enzymes, and both enzymes are susceptible to
enzyme inducers and inhibitors, which can affect the ratio of parent
drug and metabolites.
Oral pharmacokinetics result in a Tmax of <30 min and a similar
elimination half-life to that seen after intravenous administration,
consistent with the relatively short-duration of drug effect (Shram
et al., 2011b). However, larger amounts of norketamine are found
than after intravenous administration because of first pass
biotransformation of ketamine.
Few studies of ketamine's pharmacodynamics have tried to
relate the drug's kinetics to the drug effects. The different kinetics
between men and women and the potential for drug-drug in-
teractions has not been studied or discussed in the context of ke-
tamine abuse.
8.5.2. Pharmacodynamics
The cognitive and other effects of ketamine after intravenous
(target plasma concentration 0, 50, 100, 150, and 200 ng/ml),
intramuscular (0.2 and 0.4 mg/kg), subcutaneous (0.25 mg, 0.5 and
1.0 mg/kg) and oral administration (60, 120 and 150 mg) have been
studied in human volunteers (Bowdle et al., 1998; Lofwall et al.,
2006; Shram et al., 2011a, 2011b). After intravenous administra-
tion the relation of mean ketamine plasma concentrations to the
target concentrations was highly linear, with a correlation
Please cite this article in press as: Sellers, E.M., et al., Studies with psychedelic drugs in human volunteers, Neuropharmacology (2017), https://
doi.org/10.1016/j.neuropharm.2017.11.029
coefficient of R ¼ 0.997 (P ¼ 0.0027). Ketamine produced dose-
related psychedelic effects. The relation between steady-state ke-
tamine plasma concentration and VAS scores was highly linear for
all VAS items, with linear regression coefficients ranging from
R ¼ 0.93 to 0.99 (P < 0.024 to P < 0.0005). Hallucinogen rating scale
scores were similar to those found in a previous study with psy-
chedelic doses of N,N-dimethyltryptamine, an illicit LSD-25-like
drug (Bowdle et al., 1998). In contrast, low doses of intramuscular
ketamine only produced cognitive impairment relating to memory,
and no subjective effects (Lofwall et al., 2006). Subcutaneous ke-
tamine in 12 patients with refractory anxiety showed a dose related
reduction in HAM-A and a dose related increase in the Clinically
Administered Dissociative States Scale (CADSS) (Glue et al., 2017)
Ketamine is abused for its euphoric and perceptual properties.
Because it is an approved drug, Shram et al. considered that keta-
mine would make a suitable positive control in abuse potential
studies (Shram et al., 2011b). A single-center, partially double-
blind, placebo controlled, ascending dose (65, 100 and 150 mg)
trial was carried out in 11 healthy recreational polydrug users who
first passed a pharmacologic qualification session to ensure they
could distinguish and like the effects of a psychoactive drug (20 mg
D-amphetamine) compared to placebo. Subjective data were
collected through questionnaires (e.g., Addiction Research Center
Inventory [ARCI] scales) and visual analog scales (VAS). Generally,
oral ketamine was well tolerated and could be used safely at 65 mg
and 100 mg. Peak responses to ketamine were significantly
different (p < 0.05) from placebo on measures of positive (e.g., drug
liking VAS), perceptual (e.g., VAS of floating, detached, halluci-
nating) and sedative (e.g., ARCI phenobarbitale-
chlorpromazineealcohol group scale) effects. Responses were
generally not dose-dependent, though significant differences for
some subjective effects measures were observed between 65 mg
and 100 mg ketamine. This study indicated that oral ketamine
doses of 65 mg and 100 mg are useful positive controls for future
abuse potential studies of compounds with a similar mechanism of
action or with possible perception-altering and euphoric effects
(Shram et al., 2011b).
8.6. Methylenedioxymethamphetamine (MDMA) “ecstasy”
MDMA is a ring substituted amphetamine related to mescaline
and methamphetamine. The agent acts as a serotonin agonist by
both releasing serotonin and blocking its uptake and as a potent
releaser of dopamine and norepinephrine (de la Torre et al., 2004;
Farre et al., 2004, 2015; Pardo-Lozano et al., 2012; Peiro et al., 2013;
White et al., 1996). Typical effects are a combination of serotonergic
and catechol related experiences including euphoria, well-being,
happiness, increased energy, feeling close to others (entactogen),
increased sociability, enhanced mood, mild perceptual changes
(altered perception of sounds and colors) along with cardiovascular
and other autonomic changes. While derealization occurs, frank
hallucinations generally do not. Acute toxicity (lack of appetite, dry
mouth, palpitations, insomnia, and anxiety) is also observed and
reported with amphetamines. Post-dosing, subjects reported fa-
tigue, weakness, lack of energy and depressed mood (de la Torre
et al., 2004). More striking toxicity occurs with overdose and is
also primarily related to serotonin and catecholamine toxicity i.e.,
hyperthermia, muscle rigidity, hyperreflexia and cardiovascular
effects (de la Torre et al., 2004; Sellers et al., 1979). A variety of
expected hormonal and other biologic changes also occur (de la
Torre et al., 2004).
8.6.1. Pharmacokinetics
After single administration, MDMA half-life is 9.0 ± 2.3 h
(mean ± SD). Biotransformation is by cytochrome P450 2D6
 Edward.M. Sellers et al. / Neuropharmacology xxx (2017) 1e19
(CYP2D6) and catechol O-methyltransferase (COMT). CYP2D6 is a
polymorphic drug metabolizing enzyme with homozygous null
mutations conferring inactivity in about 7% of the Caucasian Eu-
ropean population. After repeated dosing the area under the
MDMA concentration curve increases due primarily to mechanism
based inhibition of CYP2D6 by MDMA (Farre et al., 2004; Yang et al.,
2006). This has the effect of blocking or decreasing MDMA meta-
bolism. This inhibition may persist for weeks. This inhibition,
resulting in non-linear pharmacokinetics, appears to be more
important than the impact of the CYP2D6 polymorphism on acute
dosing and toxicity. A further complexity arises because the activity
and biotransformation of the MDMA stereoisomers occur at
different rates (Schwaninger et al., 2011a, 2011b, 2012).
After repeated dosing even though plasma concentration rise
disproportionately most MDMA effects do not suggesting the
development of acute tolerance. The exceptions are systolic blood
pressure and reaction time which increased with dose (Farre et al.,
2015).
8.6.2. Therapeutic applications
Advocacy for the potential therapeutic utility of MDMA has
come principally from the Multidisciplinary Association for Psy-
chedelic Studies based in Santa Cruz, CA USA. (Mithoefer et al.,
2016, 2011, 2013; Yazar-Klosinski and Mithoefer, 2017). Proposed
therapeutic targets include post-traumatic stress disorder, anxiety
associated with life threatening illness, depression and social
anxiety in autistic adults. Several proof of concept trials have been
conducted (Mithoefer et al., 2011, 2013). The treatment model is
similar to other applications of hallucinogens namely, drug-assisted
structured psychotherapy in carefully selected patients, in
controlled settings with careful monitoring.
However, in addition to the noted challenges of all studies with
hallucinogens, MDMA research is further complicated by the
agent's non-linear pharmacokinetics, multiple neurotransmitter
system effects, wide range of adverse effects and a concern about
long-term neurotoxicity and chronic tolerance to the agent (Parrott,
2005, 2014a, b). MDMA has more wide-ranging effects than clas-
sical hallucinogens and shares much of the toxicity of amphet-
amines. This suggests that MDMA has a high potential to interact
with other medications and disorders and have a variety of unde-
sirable clinical effects. The human pharmacology and therapeutic
use of MDMA appears to be controversial and complex.
8.7. Dextromethorphan
Dextromethorphan (DXM) is a widely available non-
prescription anti-tussive which is subject to sporadic and episodic
abuse, primarily by adolescents who may use quite high doses
(Schadel and Sellers, 1992). Both DXM and its active metabolite
dextrorphan (DOR) are NMDA antagonists and share pharmaco-
logic properties with phencyclidine (Carter et al., 2013; Reissig
et al., 2012). DXO has a greater affinity for the NMDA receptor
and parent and metabolite have demonstrated differing pharma-
cologic profiles in humans and laboratory animals (Holtzman, 1994;
Nicholson et al., 1999; Zawertailo et al., 1998, 2010). The conversion
of DEM to DOR is primarily by the genetically polymorphic cyto-
chrome P450 2D6 enzyme (Schadel et al., 1995; Tyndale et al.,
1999). Consequently, CYP2D6 deficient individuals and those
whose enzyme has been inhibited by quinidine, clearly illustrate
the different pharmacologic effects of parent and metabolite
(Zawertailo et al., 1998, 2010). DOR has more prominent psyche-
delic properties and is identified as psilocybin-like, whereas DEM
produces more nausea and drowsiness (Zawertailo et al., 1998,
2010).
Please cite this article in press as: Sellers, E.M., et al., Studies with psychedelic drugs in human volunteers, Neuropharmacology (2017), https://
doi.org/10.1016/j.neuropharm.2017.11.029
13
8.7.1. Pharmacokinetics
The pharmacokinetics and pharmacodynamics of dextrome-
thorphan and its active metabolite dextrorphan are affected pro-
foundly by the CYP2D6 polymorphism. Poor metabolizers have 5-
fold higher concentrations of dextromethorphan compared to
extensive metabolizers. Dextrorphan concentrations in poor
metabolizers are only 3% of those in extensive metabolizers
(Zawertailo et al., 1998, 2010). These differences likely result in
large variations in the psychedelic effects of dextromethorphan in
different ethno-racial groups (Fohner et al., 2013; Griman et al.,
2012; Hicks et al., 2013; Wright et al., 2010).
8.7.2. Pharmacodynamics
Although generally few proper dose-response studies have been
conducted with psychedelic substances, dextromethorphan, an
approved therapeutic drug, is a notable exception. Single oral doses
of DEM ranging from 100 mg/70 kg to 800 mg/70 kg at 100 mg/kg
increments have been studied and compared to triazolam in 12
CYP2D6 phenotyped healthy volunteers (Reissig et al., 2012).
Triazolam produced dose-related increases in subject-rated
sedation, observer-rated sedation, and behavioral impairment.
DXM produced a profile of dose-related physiological and subjec-
tive effects differing from triazolam. DXM effects included increases
in blood pressure, heart rate, and emesis, increases in observer-
rated effects typical of classic hallucinogens (e.g. distance from
reality, visual effects with eyes open and closed, joy, anxiety), and
participant ratings of stimulation (e.g. jittery, nervous), somatic
effects (e.g. tingling, headache), perceptual changes, end-of-session
drug liking, and mystical-type experience. After 400 mg/70 kg
DXM, 11 of 12 participants indicated on a pharmacological class
questionnaire that they thought they had received a classic hallu-
cinogen (e.g. psilocybin). Drug effects resolved without significant
adverse effects by the end of the session. In a 1-month follow up
volunteers attributed increased spirituality and positive changes in
attitudes, moods, and behavior to the session experiences. High
doses, i.e. > 400 mg of DXM, were not tolerated well by some
subjects and only 2e4 subjects received each of the higher doses
which produced effects distinct from triazolam and had charac-
teristics that were like the classic hallucinogen psilocybin.
Despite some similarities of DXM effects to psilocybin and
classical hallucinogens, there were differences. High doses of DXM
produced vomiting and severe behavioral impairment and did not
result in observer reports of crying, ideas of reference and arousal
seen with psilocybin (Griffiths et al., 2011; Reissig et al., 2012).
These well conducted studies nevertheless share the scientific
and design features that limit generalizability: small numbers of
subjects; prominent expectancy effects, high reporting bias and
lack of direct comparison to other agents (Reissig et al., 2012).
8.8. Lorcaserin
The historical association of 5HT2A agonists with altered
perception and serious adverse events raises regulatory concerns
about off-target effects of agents that have activity on 5HT re-
ceptors. One such example of this concern is illustrated by lorca-
serin, developed for weight management (Shram et al., 2011a).
While lorcaserin, is a selective and potent (Ki ¼ 15 nmol/l;
EC50 ¼ 9 nmol/l) centrally acting 5HT2C receptor subtype agonist,
any 5-HT2A receptor agonist activity would have serious implica-
tions for drug scheduling, labelling and safety and would likely be
an unacceptable risk for treatment of obesity. Lorcaserin does bind
at the 5-HT2A receptor (EC50 ¼ 168 nmol/l), which might be relevant
when it is administered at supratherapeutic doses. While preclin-
ical data indicated little evidence of 5-HT2A-related pharmacolog-
ical activity by lorcaserin in vivo, a small proportion of the patients
14 Edward.M. Sellers et al. / Neuropharmacology xxx (2017) 1e19
who received supratherapeutic doses of lorcaserin in clinical trials
reported altered perception, abnormal dreams, sedation, or feelings
of euphoria (Shram et al., 2011a).
In consideration of its novel mechanism of action and the spo-
radic reports from clinical trials of adverse events that could be
associated with abuse potential, a human abuse potential study was
conducted to evaluate possible positive and perception-altering
effects of both therapeutic and supratherapeutic single oral doses
of lorcaserin as compared with placebo and two drugs with known
patterns of abuse: zolpidem and ketamine (Shram et al., 2011a).
Recreational polydrug users were selected for participation in the
study because they are from a population at higher risk for exper-
imenting with and using medications for nontherapeutic purposes
and because, given their previous experience with recreational
drugs, they can reliably rate drug effects.
This study was a double-blind, double-dummy, placebo-
controlled, randomized seven-way crossover study with single
oral doses of lorcaserin (20, 40, and 60 mg), zolpidem (15 and
30 mg), ketamine (100 mg), and placebo conducted in recreational
polydrug users (N ¼ 35). Subjective and objective measures were
assessed up to 24 h after the dose. Zolpidem and ketamine had
significantly higher peak scores relative to placebo on the primary
measures as well as on most of the secondary measures. The sub-
jective effects of a 20-mg dose of lorcaserin were like those of
placebo, whereas supratherapeutic doses of lorcaserin were asso-
ciated with significant levels of dislike by users as compared with
placebo, zolpidem, and ketamine. Perceptual effects were minimal
after administration of lorcaserin and significantly lower than after
administration of either ketamine or zolpidem. The findings sug-
gest that, at supratherapeutic doses, lorcaserin is associated with
distinct, primarily negative, subjective effects and has low abuse
potential. These data underscore the fact that many individuals,
including drug abusers, do not like alterations in perception and
find them aversive.
9. Practical and regulatory challenges
In additions to the unique scientific and study conduct chal-
lenges, there are numerous practical and regulatory considerations
to be addressed before a drug with prominent psychedelic proper-
ties will be approved (Table 7. Practical and Regulatory obstacles to
drug approval of psychedelic agents) (Sellers and Leiderman,
2017). The fundamental requirements for approval of an agent
with psychedelic properties and known potentially serious toxicity
are the same as for any other drug in development. For agents with
psychedelic/psychotomimetic properties, uncertainty about mech-
anisms of action, lack of modern pre-clinical safety data, difficulty
specifying therapeutic drug response endpoints and lack of popu-
lation based pharmacokinetics will need to be addressed.
Other regulatory compliance issues include identifying an
appropriate “unmet medical need”, conducting Phase III trials
outside of specialized academic centres and designing trials that
demonstrate the relative and unique contributions to outcome of
the psychedelic agent and the concurrent supportive care and
psychotherapy (Sellers and Leiderman, 2017).
(Sellers and Leiderman, 2017). The trial design of investigational
drug combined with structured psychotherapy is well accept-
eddand indeed has been relied upon for anti-depressant and
addiction therapeutic development. That said, the intensity of the
psychosocial and support component in the psychedelic studies
conducted to date, may have confounded the drug contribution to
the observed outcomes.
Special safety issues will have to be considered in both study
conduct and in any approval. At a minimum, in the US, REMS would
be required with Elements to Assure Safe Use likely addressing the
Please cite this article in press as: Sellers, E.M., et al., Studies with psychedelic drugs in human volunteers, Neuropharmacology (2017), https://
doi.org/10.1016/j.neuropharm.2017.11.029
qualifications of treating clinicians and treatment setting as well as
patient sections.
That psychedelics have been safely administered in small highly
controlled clinical trial academic center settings under the direc-
tion of academic experts, has limited generalizability or no appli-
cation to the substantial risk posed by psychedelic drugs used in
less controlled, supervised settings, in less carefully selected pa-
tients, or if the doses are not controlled. Hallucinogens have the
potential for serious immediate and long-term adverse neuro-
behavioral and psychiatric adverse effects. Even though, studies
have been conducted safely in carefully selected subject patients, in
vulnerable subjects (people with a pre-existent risk of mental
disease), hallucinogens may induce psychosis, confusion, impair-
ment of reasoning, regret, depression, loneliness and/or somatic
discomfort, all of which can be of monumental proportions (De
Gregorio et al., 2016). With the precautions taken in many of the
studies outlined in the chapter most of these risks can be mitigated.
Precedent exists for the development and approval of CSA
Schedule I substances (i.e., substances with the highest potential for
abuse and no known medical use). These CSA Schedule I agents
include psychotomimetic or hallucinogenic substances such as LSD,
psilocybin, DMT, MDMA cannabis and cannabis constituents
(Agency, 2017). When it has occurred, clinical trials and ultimate
approval were for serious and/or unmet medical needs. Some ex-
amples include Marinol® initially approved for AIDS related anorexia
and gamma hydroxybutyrate (GHB) Xyrem® approved for Cataplexy
in Narcolepsy (Sellers and Leiderman, 2017). Approval of such drugs
typically takes many years. In the case of Marinol®, it was 14 years
after its approval as an orphan drug for AIDS related anorexia before
it was approved for cancer chemotherapy related nausea and moved
from the CSA Schedule II to C-III. GHB was available as an uncon-
trolled chemical in the 1960s but was not an approved drug until
2004 when the approved product, Xyrem, was also placed in the CSA
Schedule III, while the substance GHB remains in Schedule I.
FDA provides several programs to facilitate new drug develop-
ment for unmet or under-met medical needs (Sellers and
Leiderman, 2017). Although special pathways appeal since they
suggest faster review, increased interaction with FDA, reduced trial
sizes, and potential market exclusivity, the data requirements
remain unchanged (Sellers and Leiderman, 2017).
10. Future research
10.1. Need for understanding the neurobiology
Additional potential benefits of ongoing basic and clinical
research with such agents may come from further elucidation of
the neurobiology of these compounds and relating this to specific
mental and behavioral disorders. Understanding the neurobiolog-
ical basis of the different clinical effects seen with the prototypic
agents in this review may suggest new specific and selective ap-
proaches to future therapeutic agents.
Considerable attention has been paid to the use of hallucinogens
as models of psychosis in humans. This has resulted in the proposal
that such modeled psychosis can be used to screen for new anti-
psychotic agents (De Gregorio et al., 2016). However, caution is
needed in concluding that a phenomenon such as LSD altered
sensorimotor gating is a human model of psychosis since it takes
one observation in isolation and does not reconcile it to the many
other phenotypic differences seen with psychosis and not seen with
hallucinogens (e.g., see Table 1. in (De Gregorio et al., 2016)).
10.2. Expand pharmacokinetics and pharmacogenomics
Limited pharmacokinetic data exist for most hallucinogens since
 Edward.M. Sellers et al. / Neuropharmacology xxx (2017) 1e19
sample sizes are small and relatively homogeneous. Larger studies
of genetically and racially diverse populations are needed. Data in
females are extremely limited as are data concerning drug-drug
interactions and effects of fasting and feeding. Whether drug con-
centrations can usefully anticipate clinical response after repeat
dosing is unknown. As for all psychoactive drugs, pharmacody-
namic variation is probably large. Genetic variants of the 5HT2A
and 2C receptors and other psychedelic drug targets are known
hence some very sensitive and insensitive individuals probably
exist. All therapeutic research targeting unmet medical needs is a
type of precision medicine since it assumes there are subsets of
individuals who will respond uniquely to the agents. Hallucinogens
research should probably routinely include comprehensive geno-
typing and try to relate it to disease phenotype. Conceivably
haplotype patterns of “super” responders may be identified.
10.3. Need to meet modern safety standards
Despite much experience with various psychedelic agents over
many years, regulatory and scientific standards have changed over
the past 60 years. These standards will need to be met. The acute
and chronic reproductive, molecular biologic and genetic toxi-
cology data are very limited for most psychedelics. Most data relate
to single doses and not multiple dose exposures. Long-term
behavioral safety in populations with risk factors and mental dis-
orders are largely unknown.
10.4. Need for comparative trials
Drug effectiveness is how well a drug performs in actual settings
of practice versus drug efficacy, which refers to its potential for
treatment in clinical trials (Gartlehner et al., 2006). Much treatment
with psychoactive agents is less than optimal due to a variety of
prescriber and patient factors (Alekhya et al., 2015; Ho et al., 2016).
While historically placebo controlled trials, have been sufficient
more typically, active control comparisons are an essential part of
Phase III studies. In the case of psychedelics, where they are used as
adjuncts to structured psychotherapy, for an unmet medical need,
two general options exist. The first is direct comparison of active
agent plus psychotherapy to psychotherapy alone or second,
comparison of active agent plus psychotherapy to another phar-
macotherapy. Since approved pharmacotherapy options exist for
virtually all the potential therapeutic areas being considered for
psychedelics, probably both types of studies are needed. Cochrane
or similar critical reviews can serve as a basis for selecting the most
appropriate comparator (Stein et al., 2006). When there is no
approved or appropriate pharmacologic comparator then a psy-
chotherapeutic control alone could be used.
10.5. Comparisons of psychedelic agents
Few direct comparative studies have been conducted between
and among psychedelic substances, hence understanding about
their relative effects and dose-response properties is based on cross
study conclusions. More direct comparisons of psychedelics with
different and similar putative mechanisms might define margins of
safety and isolate desired therapeutic features. In the absence of
targeted funding from Federal Agencies or Foundations for such
studies, it seems unlikely these needed studies will be conducted.
10.6. Adjunctive psychotherapy
A wide variety of types and intensities pf psychotherapy have
been used with psychedelics. Future research should attempt to
standardize and specify the form and intensity and determine what
Please cite this article in press as: Sellers, E.M., et al., Studies with psychedelic drugs in human volunteers, Neuropharmacology (2017), https://
doi.org/10.1016/j.neuropharm.2017.11.029
15
approach would be most effective and appropriate for clinical
application. In many studies one gets the impression that sup-
portive care and therapy were being given by a team of very
experienced and elite therapists. It will be important to establish an
exportable and practical psychotherapy approach for any future
therapeutic application.
10.7. Dose ranging
Studies to date have identified safe and in some cases potentially
effective doses for select therapeutic targets. The defining of lowest
effective, usually effective and maximally effective and tolerated
doses will be needed for entry to Phase III trials and future drug
labeling.
10.8. Assessment of abuse potential
Most hallucinogens are illicit and hence controlled in Schedule I
of the (US) CSA. However, none have had the range of studies
required to meet the FDA requirements for full characterization of
abuse potential in drug development for a therapeutic indication
(2017a). Since abuse potential is a type of safety assessment that
impacts not only scheduling but also labeling particularly for safety
(adverse event section of the label), and may involve warnings and
instruction on safe use, formal abuse potential studies will likely be
required (2017a).
11. Conclusions
Scientific curiosity and fascination have played a key role in
human research with psychedelics along with the hope that
perceptual alterations and heightened insight could benefit well-
being and play a role in the treatment of various neuropsychiatric
disorders. These motivations need to be tempered by a realistic
assessment of the hurdles to be cleared for therapeutic use.
Development of a psychedelic drug for treatment of a serious
psychiatric disorder presents substantial although not insur-
mountable challenges.
While the varied psychedelic agents described in this chapter
share some properties, they have a range of pharmacologic effects
that are reflected in the gradation in intensity of hallucinogenic
effects from the classical agents to DMT, MDMA, ketamine, dex-
tromethorphan and new drugs with activity in the serotonergic
system. The common link seems to be serotonergic effects modu-
lated by NMDA and other neurotransmitters. The range of halluci-
nogens available suggest that they are distinct pharmacologic
agents and will not be equally safe or effective as therapeutic tar-
gets. Newly synthesized specific and selective agents modeled on
the legacy agents may be worth evaluating.
In this chapter, we have reviewed the published scientific
literature regarding the pharmacology and attempted therapeutic
applications of psychedelic drugs. Nevertheless, in the broader
context of recent societal trends some reconsideration, with a social
context in mind, may be needed about research endeavors with
these compounds. A recent article chronicles how beliefs have
increasingly become accepted as facts by large segments of society
and have become an accepted basis for action (Andersen, 2017).
Therapeutics and science are not immune to this lack of an evi-
dence based foundation. Fascination, bias, expectancy, despair and
hope could all be sufficient basis for fostering a wish, belief or
attraction for something better or different. The history of treat-
ments for mental disorders suggests that alteration of behaviors,
thoughts, moods and improved function are partial and only sus-
tained with continuous management. This is hardly surprising
considering the complexity of etiology and the multiple factors
16 Edward.M. Sellers et al. / Neuropharmacology xxx (2017) 1e19
implicated in mental disorders and affecting outcome. Some sci-
entists, advocates and patients believe psychedelics are a “break-
through” approach to treating mental disorders (2017b; Kleber,
2016; Nutt, 2016). However, psychedelics are unlikely to be the
exception to past experience in the treatment of mental disorders.
Given the numerous challenges in developing and deploying psy-
chedelics, consideration of alternatives seems warranted. For
example, psychotherapy and meditation can provide effective
insight and management strategies for behaviors, thoughts and
moods. These can be easily made available (Vieira et al., 2017). The
rapid advances in virtual reality may also be able to provide an
experience like that created by psychedelics. Virtual reality has
been used in the management of anxiety disorders, pain, PTSD,
depressed mood (Cuijpers et al., 2017; Gaggioli et al., 2014; McLay
et al., 2014; Wiederhold et al., 2014a, 2014b). These approaches
may be better prospects for therapeutics than psychedelics with all
their challenges.
Disclosures
Dr. Sellers is Professor Emeritus at the University of Toronto. In
addition, he is a Principal in DL Global Partners Inc. DL Global
provides independent consultation to the pharmaceutical and de-
vice industry concerning psychotropic drug development and
assessment of abuse potential. He has no conflict of interest con-
cerning development of psychedelic drugs.
Dr. Romach is a Professor at the University of Toronto and a
Principal in DL Global Partners Inc. She is a staff psychiatrist in the
Perinatal Mental Health Unit, Mount Sinai Hospital, Toronto and
the Medical Director of the Ukraine Pediatric Fellowship Program,
Centre for Global Child Health, Sick Kids Hospital, Toronto. She has
no conflict of interest concerning development of psychedelic
drugs.
Dr. Leiderman, Principal at CNS Drug Consulting LLC, Board
Certified Neurologist and Fellow, American Academy of Neurology,
is the former Director, Controlled Substance Staff, CDER/FDA. She
provides consultation in drug development, and regulatory strat-
egy through an independent consultancy. Formerly Clinical Trials
program director at NIDA/NIH, as well as a Consultant Neurologist
within the VA Medical System and the US Public Health Service/
Indian Health Service, she has held academic appointments in the
Departments of Neurology at the University of Michigan and Uni-
formed Services University of the Health Sciences. She has no
conflict of interest concerning development of psychedelic drugs.
Appendix A. Supplementary data
Supplementary data related to this article can be found at
https://doi.org/10.1016/j.neuropharm.2017.11.029.
References
Agency, D.E., 2017. Controlled Substances Act - Listed Substances.
Alekhya, P., Sriharsha, M., Venkata Ramudu, R., Shivanandh, B., Priya Darsini, T.,
Reddy, K.S.K., Hrushikesh Reddy, Y., 2015. Adherence to antidepressant therapy:
sociodemographic factor wise distribution. Int. J. Pharm. Clin. Res. 7, 180e184.
Andersen, K., 2017. How America Lost its Mind. Atlantic. Hayley Romer, Washington,
DC, pp. 76e91.
Anonymous, 2017.
2017a. Assessment of abuse potential of drugs. 103rd Annual meeting of the
American society ….
Baggott, M.J., Erowid, E., Erowid, F., Galloway, G.P., Mendelson, J., 2010. Use patterns
and self-reported effects of Salvia divinorum: an internet-based survey. Drug
Alcohol Depend. 111, 250e256.
Barrett, F.S., Johnson, M.W., Griffiths, R.R., 2015. Validation of the revised Mystical
Experience Questionnaire in experimental sessions with psilocybin.
J. Psychopharmacol. 29, 1182e1190.
Berman, R.M., Cappiello, A., Anand, A., Oren, D.A., Heninger, G.R., Charney, D.S.,
Krystal, J.H., 2000. Antidepressant effects of ketamine in depressed patients.
Please cite this article in press as: Sellers, E.M., et al., Studies with psychedelic drugs in human volunteers, Neuropharmacology (2017), https://
doi.org/10.1016/j.neuropharm.2017.11.029
Biol. Psychiatry 47, 351e354.
Bogenschutz, M.P., Forcehimes, A.A., Pommy, J.A., Wilcox, C.E., Barbosa, P.C.,
Strassman, R.J., 2015. Psilocybin-assisted treatment for alcohol dependence: a
proof-of-concept study. J. Psychopharmacol. 29, 289e299.
Bowdle, T.A., Radant, A.D., Cowley, D.S., Kharasch, E.D., Strassman, R.J., Roy-
Byrne, P.P., 1998. Psychedelic effects of ketamine in healthy volunteers: rela-
tionship to steady-state plasma concentrations. Anesthesiology 88, 82e88.
Breckenridge, A., Grobbee, D.E., 2016. Psilocybin: promising results in double-blind
trials require confirmation by real-world evidence. J. Psychopharmacol. 30,
1218e1219.
Busto, U.E., Zawertailo, L.A., Kaplan, H.L., Sellers, E.M., 1999. Identifying appropriate
subjects for abuse liability studies using prestudy pharmacological testing. Can.
J. Clin. Pharmacol. 6, 103e110.
Carhart-Harris, R.L., Williams, T.M., Sessa, B., Tyacke, R.J., Rich, A.S., Feilding, A.,
Nutt, D.J., 2011. The administration of psilocybin to healthy, hallucinogen-
experienced volunteers in a mock-functional magnetic resonance imaging
environment: a preliminary investigation of tolerability. J. Psychopharmacol.
25, 1562e1567.
Carhart-Harris, R.L., Erritzoe, D., Williams, T., Stone, J.M., Reed, L.J., Colasanti, A.,
Tyacke, R.J., Leech, R., Malizia, A.L., Murphy, K., Hobden, P., Evans, J., Feilding, A.,
Wise, R.G., Nutt, D.J., 2012a. Neural correlates of the psychedelic state as
determined by fMRI studies with psilocybin. Proc. Natl. Acad. Sci. U. S. A. 109,
2138e2143.
Carhart-Harris, R.L., Leech, R., Williams, T.M., Erritzoe, D., Abbasi, N., Bargiotas, T.,
Hobden, P., Sharp, D.J., Evans, J., Feilding, A., Wise, R.G., Nutt, D.J., 2012b. Im-
plications for psychedelic-assisted psychotherapy: functional magnetic reso-
nance imaging study with psilocybin. Br. J. Psychiatry 200, 238e244.
Carhart-Harris, R.L., Leech, R., Erritzoe, D., Williams, T.M., Stone, J.M., Evans, J.,
Sharp, D.J., Feilding, A., Wise, R.G., Nutt, D.J., 2013. Functional connectivity
measures after psilocybin inform a novel hypothesis of early psychosis. Schiz-
ophr. Bull. 39, 1343e1351.
Carhart-Harris, R.L., Bolstridge, M., Rucker, J., Day, C.M., Erritzoe, D., Kaelen, M.,
Bloomfield, M., Rickard, J.A., Forbes, B., Feilding, A., Taylor, D., Pilling, S.,
Curran, V.H., Nutt, D.J., 2016. Psilocybin with psychological support for
treatment-resistant depression: an open-label feasibility study. Lancet Psychi-
atry 3, 619e627.
Carroll, M.E., 1990. PCP and hallucinogens. Adv. Alcohol Subst. Abuse 9, 167e190.
Carter, L.P., Reissig, C.J., Johnson, M.W., Klinedinst, M.A., Griffiths, R.R., Mintzer, M.Z.,
2013. Acute cognitive effects of high doses of dextromethorphan relative to
triazolam in humans. Drug Alcohol Depend. 128, 206e213.
Cochran, D.M., Fallon, D., Hill, M., Frazier, J.A., 2013. The role of oxytocin in psy-
chiatric disorders: a review of biological and therapeutic research findings.
Harv Rev. Psychiatry 21, 219e247.
Cruz, A., Domingos, S., Gallardo, E., Martinho, A., 2017. A unique natural selective
kappa-opioid receptor agonist, salvinorin A, and its roles in human therapeu-
tics. Phytochemistry 137, 9e14.
Cuijpers, P., Kleiboer, A., Karyotaki, E., Riper, H., 2017. Internet and mobile in-
terventions for depression: opportunities and challenges. Depress Anxiety 34,
596e602.
Danforth, A.L., Struble, C.M., Yazar-Klosinski, B., Grob, C.S., 2016. MDMA-assisted
therapy: a new treatment model for social anxiety in autistic adults. Prog.
Neuropsychopharmacol. Biol. Psychiatry 64, 237e249.
Davis, W., 1996. One River. Simon & Schuster, London.
De Gregorio, D., Comai, S., Posa, L., Gobbi, G., 2016. D-lysergic acid diethylamide
(LSD) as a model of psychosis: mechanism of action and pharmacology. Int. J.
Mol. Sci. 17.
de la Torre, R., Farre, M., Roset, P.N., Pizarro, N., Abanades, S., Segura, M., Segura, J.,
Cami, J., 2004. Human pharmacology of MDMA: pharmacokinetics, metabolism,
and disposition. Ther. Drug Monit. 26, 137e144.
Dolder, P.C., Schmid, Y., Haschke, M., Rentsch, K.M., Liechti, M.E., 2015. Pharmaco-
kinetics and concentration-effect relationship of oral LSD in humans. Int. J.
Neuropsychopharmacol. 19.
Enwikipediaorg, 2017. Psilocybin.
Farre, M., de la Torre, R., Mathuna, B.O., Roset, P.N., Peiro, A.M., Torrens, M.,
Ortuno, J., Pujadas, M., Cami, J., 2004. Repeated doses administration of MDMA
in humans: pharmacological effects and pharmacokinetics. Psychopharmacol.
Berl. 173, 364e375.
Farre, M., Tomillero, A., Perez-Mana, C., Yubero, S., Papaseit, E., Roset, P.N.,
Pujadas, M., Torrens, M., Cami, J., de la Torre, R., 2015. Human pharmacology of
3,4-methylenedioxymethamphetamine (MDMA, ecstasy) after repeated doses
taken 4 h apart Human pharmacology of MDMA after repeated doses taken 4 h
apart. Eur. Neuropsychopharmacol. 25, 1637e1649.
Feder, A., Parides, M.K., Murrough, J.W., Perez, A.M., Morgan, J.E., Saxena, S.,
Kirkwood, K., Aan Het Rot, M., Lapidus, K.A., Wan, L.B., Iosifescu, D.,
Charney, D.S., 2014. Efficacy of intravenous ketamine for treatment of chronic
posttraumatic stress disorder: a randomized clinical trial. JAMA Psychiatry 71,
681e688.
Fohner, A., Muzquiz, L.I., Austin, M.A., Gaedigk, A., Gordon, A., Thornton, T.,
Rieder, M.J., Pershouse, M.A., Putnam, E.A., Howlett, K., Beatty, P., Thummel, K.E.,
Woodahl, E.L., 2013. Pharmacogenetics in American indian populations: anal-
ysis of CYP2D6, CYP3A4, CYP3A5, and CYP2C9 in the confederated salish and
kootenai tribes. Pharmacogenet Genomics 23, 403e414.
Gaggioli, A., Pallavicini, F., Morganti, L., Serino, S., Scaratti, C., Briguglio, M.,
Crifaci, G., Vetrano, N., Giulintano, A., Bernava, G., Tartarisco, G., Pioggia, G.,
Raspelli, S., Cipresso, P., Vigna, C., Grassi, A., Baruffi, M., Wiederhold, B., Riva, G.,
 Edward.M. Sellers et al. / Neuropharmacology xxx (2017) 1e19
2014. Experiential virtual scenarios with real-time monitoring (interreality) for
the management of psychological stress: a block randomized controlled trial.
J. Med. Internet Res. 16, e167.
Garcia-Romeu, A., Griffiths, R.R., Johnson, M.W., 2014. Psilocybin-occasioned
mystical experiences in the treatment of tobacco addiction. Curr. Drug Abuse
Rev. 7, 157e164.
Gartlehner, G., Hansen, R.A., Nissman, D., Lohr, K.N., Carey, T.S., 2006. AHRQ Tech-
nical Reviews. Criteria for Distinguishing Effectiveness from Efficacy Trials in
Systematic Reviews. Agency for Healthcare Research and Quality (US), Rockville
(MD).
Gasser, P., Holstein, D., Michel, Y., Doblin, R., Yazar-Klosinski, B., Passie, T.,
Brenneisen, R., 2014. Safety and efficacy of lysergic acid diethylamide-assisted
psychotherapy for anxiety associated with life-threatening diseases. J. Nerv.
Ment. Dis. 202, 513e520.
Geyer, M.A., 2015. Lysergic acid diethylamide and psilocybin revisited. Biol. Psy-
chiatry 78, 516e518.
Glue, P., Medlicott, N.J., Harland, S., Neehoff, S., Anderson-Fahey, B., Le Nedelec, M.,
Gray, A., McNaughton, N., 2017. Ketamine's dose-related effects on anxiety
symptoms in patients with treatment refractory anxiety disorders.
J. Psychopharmacol. 269881117705089.
Griffiths, R.R., Richards, W.A., McCann, U., Jesse, R., 2006. Psilocybin can occasion
mystical-type experiences having substantial and sustained personal meaning
and spiritual significance. Psychopharmacol. Berl. 187, 284e292, 268-283;
discussion.
Griffiths, R., Richards, W., Johnson, M., McCann, U., Jesse, R., 2008. Mystical-type
experiences occasioned by psilocybin mediate the attribution of personal
meaning and spiritual significance 14 months later. J. Psychopharmacol. 22,
621e632.
Griffiths, R.R., Johnson, M.W., Richards, W.A., Richards, B.D., McCann, U., Jesse, R.,
2011. Psilocybin occasioned mystical-type experiences: immediate and per-
sisting dose-related effects. Psychopharmacol. Berl. 218, 649e665.
Griffiths, R.R., Johnson, M.W., Carducci, M.A., Umbricht, A., Richards, W.A.,
Richards, B.D., Cosimano, M.P., Klinedinst, M.A., 2016. Psilocybin produces
substantial and sustained decreases in depression and anxiety in patients with
life-threatening cancer: a randomized double-blind trial. J. Psychopharmacol.
30, 1181e1197.
Griman, P., Moran, Y., Valero, G., Loreto, M., Borjas, L., Chiurillo, M.A., 2012. CYP2D6
gene variants in urban/admixed and Amerindian populations of Venezuela:
pharmacogenetics and anthropological implications. Ann. Hum. Biol. 39,
137e142.
Haertzen, C.A., 1966. Development of scales based on patterns of drug effects, using
the addiction Research Center Inventory (ARCI). Psychol. Rep. 18, 163e194.
Haertzen, C.A., Hill, H.E., Belleville, R.E., 1963. Development of the addiction
research center inventory (arci): selection of items that are sensitive to the
effects of various drugs. Psychopharmacologia 4, 155e166.
Hasler, F., Bourquin, D., Brenneisen, R., Bar, T., Vollenweider, F.X., 1997. Determina-
tion of psilocin and 4-hydroxyindole-3-acetic acid in plasma by HPLC-ECD and
pharmacokinetic profiles of oral and intravenous psilocybin in man. Pharm.
Acta Helv. 72, 175e184.
Hendricks, P.S., Johnson, M.W., Griffiths, R.R., 2015. Psilocybin, psychological
distress, and suicidality. J. Psychopharmacol. 29, 1041e1043.
Hicks, J.K., Swen, J.J., Thorn, C.F., Sangkuhl, K., Kharasch, E.D., Ellingrod, V.L.,
Skaar, T.C., Muller, D.J., Gaedigk, A., Stingl, J.C., Clinical Pharmacogenetics
Implementation, C, 2013. Clinical Pharmacogenetics Implementation Con-
sortium guideline for CYP2D6 and CYP2C19 genotypes and dosing of tricyclic
antidepressants. Clin. Pharmacol. Ther. 93, 402e408.
Ho, S.C., Chong, H.Y., Chaiyakunapruk, N., Tangiisuran, B., Jacob, S.A., 2016. Clinical
and economic impact of non-adherence to antidepressants in major depressive
disorder: a systematic review. J. Affect Disord. 193, 1e10.
Holland, M.G., Ferner, R.E., 2017. A systematic review of the evidence for acute
tolerance to alcohol - the "Mellanby effect". Clin. Toxicol. (Phila) 55, 545e556.
Hollister, L.E., 1968. Chemical Psychoses. In: Thomas, Charles C. (Ed.). Springfield, IL.
Holtzman, S.G., 1994. Discriminative stimulus effects of dextromethorphan in the
rat. Psychopharmacol. Berl. 116, 249e254.
Hooker, J.M., Xu, Y., Schiffer, W., Shea, C., Carter, P., Fowler, J.S., 2008. Pharmacoki-
netics of the potent hallucinogen, salvinorin A in primates parallels the rapid
onset and short duration of effects in humans. Neuroimage 41, 1044e1050.
Jacob 3rd, P., Shulgin, A.T., 1994. Structure-activity relationships of the classic hal-
lucinogens and their analogs. NIDA Res. Monogr. 146, 74e91.
Johnson, M.W., Griffiths, R.R., 2013. Comparative abuse liability of GHB and ethanol
in humans. Exp. Clin. Psychopharmacol. 21, 112e123.
Johnson, M., Richards, W., Griffiths, R., 2008. Human hallucinogen research:
guidelines for safety. J. Psychopharmacol. 22, 603e620.
Johnson, M.W., MacLean, K.A., Reissig, C.J., Prisinzano, T.E., Griffiths, R.R., 2011.
Human psychopharmacology and dose-effects of salvinorin A, a kappa opioid
agonist hallucinogen present in the plant Salvia divinorum. Drug Alcohol
Depend. 115, 150e155.
Johnson, M.W., Sewell, R.A., Griffiths, R.R., 2012. Psilocybin dose-dependently cau-
ses delayed, transient headaches in healthy volunteers. Drug Alcohol Depend.
123, 132e140.
Johnson, M.W., Garcia-Romeu, A., Cosimano, M.P., Griffiths, R.R., 2014. Pilot study of
the 5-HT2AR agonist psilocybin in the treatment of tobacco addiction.
J. Psychopharmacol. 28, 983e992.
Johnson, M.W., MacLean, K.A., Caspers, M.J., Prisinzano, T.E., Griffiths, R.R., 2016.
Time course of pharmacokinetic and hormonal effects of inhaled high-dose
Please cite this article in press as: Sellers, E.M., et al., Studies with psychedelic drugs in human volunteers, Neuropharmacology (2017), https://
doi.org/10.1016/j.neuropharm.2017.11.029
17
salvinorin A in humans. J. Psychopharmacol. 30, 323e329.
Johnson, M.W., Garcia-Romeu, A., Griffiths, R.R., 2017. Long-term follow-up of
psilocybin-facilitated smoking cessation. Am. J. Drug Alcohol Abuse 43, 55e60.
Kalant, H., 1998. Research on tolerance: what can we learn from history? Alcohol
Clin. Exp. Res. 22, 67e76.
Kleber, H.D., 2016. The successful return of psychedelics to psychiatry.
J. Psychopharmacol. 30, 1211.
Koenig, X., Hilber, K., 2015. The anti-addiction drug ibogaine and the heart: a
delicate relation. Molecules 20, 2208e2228.
Kometer, M., Schmidt, A., Bachmann, R., Studerus, E., Seifritz, E., Vollenweider, F.X.,
2012. Psilocybin biases facial recognition, goal-directed behavior, and mood
state toward positive relative to negative emotions through different seroto-
nergic subreceptors. Biol. Psychiatry 72, 898e906.
Kometer, M., Pokorny, T., Seifritz, E., Volleinweider, F.X., 2015. Psilocybin-induced
spiritual experiences and insightfulness are associated with synchronization of
neuronal oscillations. Psychopharmacol. Berl. 232, 3663e3676.
Krupitsky, E.M., Grinenko, A.Y., 1997. Ketamine psychedelic therapy (KPT): a review
of the results of ten years of research. J. Psychoact. Drugs 29, 165e183.
Krupitsky, E., Burakov, A., Romanova, T., Dunaevsky, I., Strassman, R., Grinenko, A.,
2002. Ketamine psychotherapy for heroin addiction: immediate effects and
two-year follow-up. J. Subst. Abuse Treat. 23, 273e283.
Krupitsky, E.M., Burakov, A.M., Dunaevsky, I.V., Romanova, T.N., Slavina, T.Y.,
Grinenko, A.Y., 2007. Single versus repeated sessions of ketamine-assisted
psychotherapy for people with heroin dependence. J. Psychoact. Drugs 39,
13e19.
Kupferschmidt, K., 2014. High hopes. Science 345, 18e23.
Le, A.D., Kalant, H., 1990. Learning as a factor in ethanol tolerance. NIDA Res.
Monogr. 97, 193e207.
Lofwall, M.R., Griffiths, R.R., Mintzer, M.Z., 2006. Cognitive and subjective acute
dose effects of intramuscular ketamine in healthy adults. Exp. Clin. Psycho-
pharmacol. 14, 439e449.
MacLean, K.A., Johnson, M.W., Griffiths, R.R., 2011. Mystical experiences occasioned
by the hallucinogen psilocybin lead to increases in the personality domain of
openness. J. Psychopharmacol. 25, 1453e1461.
MacLean, K.A., Johnson, M.W., Reissig, C.J., Prisinzano, T.E., Griffiths, R.R., 2013.
Dose-related effects of salvinorin A in humans: dissociative, hallucinogenic, and
memory effects. Psychopharmacol. Berl. 226, 381e392.
Maqueda, A.E., Valle, M., Addy, P.H., Antonijoan, R.M., Puntes, M., Coimbra, J.,
Ballester, M.R., Garrido, M., Gonzalez, M., Claramunt, J., Barker, S.,
Johnson, M.W., Griffiths, R.R., Riba, J., 2015. Salvinorin-a induces intense
dissociative effects, blocking external sensory perception and modulating
interoception and sense of body ownership in humans. Int. J. Neuro-
psychopharmacol. 18.
Maqueda, A.E., Valle, M., Addy, P.H., Antonijoan, R.M., Puntes, M., Coimbra, J.,
Ballester, M.R., Garrido, M., Gonzalez, M., Claramunt, J., Barker, S., Lomnicka, I.,
Waguespack, M., Johnson, M.W., Griffiths, R.R., Riba, J., 2016. Naltrexone but not
ketanserin Antagonizes the subjective, cardiovascular, and neuroendocrine ef-
fects of salvinorin-a in humans. Int. J. Neuropsychopharmacol. 19.
Martin, W.R., Sloan, J.W., Sapira, J.D., Jasinski, D.R., 1971. Physiologic, subjective, and
behavioral effects of amphetamine, methamphetamine, ephedrine, phenmet-
razine, and methylphenidate in man. Clin. Pharmacol. Ther. 12, 245e258.
McCorvy, J.D., Olsen, R.H., Roth, B.L., 2016. Psilocybin for depression and anxiety
associated with life-threatening illnesses. J. Psychopharmacol. 30, 1209e1210.
McLay, R., Ram, V., Murphy, J., Spira, J., Wood, D.P., Wiederhold, M.D.,
Wiederhold, B.K., Johnston, S., Reeves, D., 2014. Effect of virtual reality PTSD
treatment on mood and neurocognitive outcomes. Cyberpsychol Behav. Soc.
Netw. 17, 439e446.
Mithoefer, M.C., Wagner, M.T., Mithoefer, A.T., Jerome, L., Doblin, R., 2011. The safety
and efficacy of {þ/-}3,4-methylenedioxymethamphetamine-assisted psycho-
therapy in subjects with chronic, treatment-resistant posttraumatic stress
disorder: the first randomized controlled pilot study. J. Psychopharmacol. 25,
439e452.
Mithoefer, M.C., Wagner, M.T., Mithoefer, A.T., Jerome, L., Martin, S.F., Yazar-
Klosinski, B., Michel, Y., Brewerton, T.D., Doblin, R., 2013. Durability of
improvement in post-traumatic stress disorder symptoms and absence of
harmful effects or drug dependency after 3,4-
methylenedioxymethamphetamine-assisted psychotherapy: a prospective
long-term follow-up study. J. Psychopharmacol. 27, 28e39.
Mithoefer, M.C., Grob, C.S., Brewerton, T.D., 2016. Novel psychopharmacological
therapies for psychiatric disorders: psilocybin and MDMA. Lancet Psychiatry 3,
481e488.
2017b. Molly at the marriott: inside America's premier psychedelics conference.
Naranjo, C., Shulgin, A.T., Sargent, T., 1967. Evaluation of 3,4-
methylenedioxyamphetamine (MDA) as an adjunct to psychotherapy. Med.
Pharmacol. Exp. Int. J. Exp. Med. 17, 359e364.
Nichols, D.E., 2016. Psychedelics. Pharmacol. Rev. 68, 264e355.
Nicholson, K.L., Hayes, B.A., Balster, R.L., 1999. Evaluation of the reinforcing prop-
erties and phencyclidine-like discriminative stimulus effects of dextromethor-
phan and dextrorphan in rats and rhesus monkeys. Psychopharmacol. Berl. 146,
49e59.
Niesters, M., Dahan, A., 2012. Pharmacokinetic and pharmacodynamic consider-
ations for NMDA receptor antagonists in the treatment of chronic neuropathic
pain. Expert Opin. Drug Metab. Toxicol. 8, 1409e1417.
Nutt, D., 2016. Psilocybin for anxiety and depression in cancer care? Lessons from
the past and prospects for the future. J. Psychopharmacol. 30, 1163e1164.
18 Edward.M. Sellers et al. / Neuropharmacology xxx (2017) 1e19
Nutt, D.J., King, L.A., Nichols, D.E., 2013. Effects of Schedule I drug laws on neuro-
science research and treatment innovation. Nat. Rev. Neurosci. 14, 577e585.
Osmond, H., 1957. A review of the clinical effects of psychotomimetic agents. Ann. N.
Y. Acad. Sci. 66, 418e434.
Ostuzzi, G., Matcham, F., Dauchy, S., Barbui, C., Hotopf, M., 2015. Antidepressants for
the treatment of depression in people with cancer. Cochrane Database Syst. Rev.
Cd011006.
Pardo-Lozano, R., Farre, M., Yubero-Lahoz, S., O'Mathuna, B., Torrens, M.,
Mustata, C., Perez-Mana, C., Langohr, K., Cuyas, E., Carbo, M., de la Torre, R.,
2012. Clinical pharmacology of 3,4-methylenedioxymethamphetamine (MDMA,
"ecstasy"): the influence of gender and genetics (CYP2D6, COMT, 5-HTT). PLoS
One 7, e47599.
Parrott, A.C., 2005. Chronic tolerance to recreational MDMA (3,4-
methylenedioxymethamphetamine) or Ecstasy. J. Psychopharmacol. 19, 71e83.
Parrott, A.C., 2014a. MDMA is certainly damaging after 25 years of empirical
research: a reply and refutation of Doblin et al. (2014). Hum. Psychopharmacol.
29, 109e119.
Parrott, A.C., 2014b. The potential dangers of using MDMA for psychotherapy.
J. Psychoact. Drugs 46, 37e43.
Passie, T., Seifert, J., Schneider, U., Emrich, H.M., 2002. The pharmacology of psilo-
cybin. Addict. Biol. 7, 357e364.
Peiro, A.M., Farre, M., Roset, P.N., Carbo, M., Pujadas, M., Torrens, M., Cami, J., de la
Torre, R., 2013. Human pharmacology of 3,4-
methylenedioxymethamphetamine (MDMA, ecstasy) after repeated doses
taken 2 h apart. Psychopharmacol. Berl. 225, 883e893.
Reissig, C.J., Carter, L.P., Johnson, M.W., Mintzer, M.Z., Klinedinst, M.A., Griffiths, R.R.,
2012. High doses of dextromethorphan, an NMDA antagonist, produce effects
similar to classic hallucinogens. Psychopharmacol. Berl. 223, 1e15.
Riba, J., McIlhenny, E.H., Bouso, J.C., Barker, S.A., 2015. Metabolism and urinary
disposition of N,N-dimethyltryptamine after oral and smoked administration: a
comparative study. Drug Test. Anal. 7, 401e406.
Rodriguez, C.I., Kegeles, L.S., Levinson, A., Feng, T., Marcus, S.M., Vermes, D., Flood, P.,
Simpson, H.B., 2013. Randomized controlled crossover trial of ketamine in
obsessive-compulsive disorder: proof-of-concept. Neuropsychopharmacology
38, 2475e2483.
Roseman, L., Leech, R., Feilding, A., Nutt, D.J., Carhart-Harris, R.L., 2014. The effects of
psilocybin and MDMA on between-network resting state functional connec-
tivity in healthy volunteers. Front. Hum. Neurosci. 8, 204.
Ross, S., Bossis, A., Guss, J., Agin-Liebes, G., Malone, T., Cohen, B., Mennenga, S.E.,
Belser, A., Kalliontzi, K., Babb, J., Su, Z., Corby, P., Schmidt, B.L., 2016. Rapid and
sustained symptom reduction following psilocybin treatment for anxiety and
depression in patients with life-threatening cancer: a randomized controlled
trial. J. Psychopharmacol. 30, 1165e1180.
Roth, B.L., Baner, K., Westkaemper, R., Siebert, D., Rice, K.C., Steinberg, S.,
Ernsberger, P., Rothman, R.B., 2002. Salvinorin A: a potent naturally occurring
nonnitrogenous kappa opioid selective agonist. Proc. Natl. Acad. Sci. U. S. A. 99,
11934e11939.
Sanacora, G., Frye, M.A., McDonald, W., Mathew, S.J., Turner, M.S., Schatzberg, A.F.,
Summergrad, P., Nemeroff, C.B., American Psychiatric Association Council of
Research Task Force on Novel, B., Treatments, 2017. A Consensus Statement on
the Use of Ketamine in the Treatment of Mood Disorders. JAMA Psychiatry 74,
399e405.
Schadel, M., Sellers, E.M., 1992. Psychosis with vicks formula 44-d abuse. Cmaj 147,
843e844.
Schadel, M., Wu, D., Otton, S.V., Kalow, W., Sellers, E.M., 1995. Pharmacokinetics of
dextromethorphan and metabolites in humans: influence of the CYP2D6
phenotype and quinidine inhibition. J. Clin. Psychopharmacol. 15, 263e269.
Schak, K.M., Vande Voort, J.L., Johnson, E.K., Kung, S., Leung, J.G., Rasmussen, K.G.,
Palmer, B.A., Frye, M.A., 2016. Potential risks of poorly monitored ketamine use
in depression treatment. Am. J. Psychiatry 173, 215e218.
Schmid, Y., Enzler, F., Gasser, P., Grouzmann, E., Preller, K.H., Vollenweider, F.X.,
Brenneisen, R., Muller, F., Borgwardt, S., Liechti, M.E., 2015. Acute effects of
lysergic acid diethylamide in healthy subjects. Biol. Psychiatry 78, 544e553.
Schwaninger, A.E., Meyer, M.R., Barnes, A.J., Kolbrich-Spargo, E.A., Gorelick, D.A.,
Goodwin, R.S., Huestis, M.A., Maurer, H.H., 2011a. Urinary excretion kinetics of
3,4-methylenedioxymethamphetamine (MDMA, ecstasy) and its phase I and
phase II metabolites in humans following controlled MDMA administration.
Clin. Chem. 57, 1748e1756.
Schwaninger, A.E., Meyer, M.R., Maurer, H.H., 2011b. Investigation on the enantio-
selectivity of the sulfation of the methylenedioxymethamphetamine metabo-
lites 3,4-dihydroxymethamphetamine and 4-hydroxy-3-
methoxymethamphetamine using the substrate-depletion approach. Drug
Metab. Dispos. 39, 1998e2002.
Schwaninger, A.E., Meyer, M.R., Barnes, A.J., Kolbrich-Spargo, E.A., Gorelick, D.A.,
Goodwin, R.S., Huestis, M.A., Maurer, H.H., 2012. Stereoselective urinary MDMA
(ecstasy) and metabolites excretion kinetics following controlled MDMA
administration to humans. Biochem. Pharmacol. 83, 131e138.
Sellers, E.M., 2017a. Deconstructing designer drugs. Clin. Pharmacol. Ther. 101,
167e169.
Sellers, E.M., 2017b. Psilocybin: good trip or bad trip. Clin. Pharmacol. Ther. 102,
580e584.
Sellers, E.M., Leiderman, D.B., 2017. Psychedelic drugs as therapeutics: no illusions
about the challenges. Clin. Pharmacol. Ther. https://doi.org/10.1002/cpt.776.
Sellers, E.M., Carr, G., Bernstein, J.G., Sellers, S., Koch-Weser, J., 1972a. Interaction of
chloral hydrate and ethanol in man. II. Hemodynamics and performance. Clin.
Please cite this article in press as: Sellers, E.M., et al., Studies with psychedelic drugs in human volunteers, Neuropharmacology (2017), https://
doi.org/10.1016/j.neuropharm.2017.11.029
Pharmacol. Ther. 13, 50e58.
Sellers, E.M., Lang, M., Koch-Weser, J., LeBlanc, E., Kalant, H., 1972b. Interaction of
chloral hydrate and ethanol in man. I. Metabolism. Clin. Pharmacol. Ther. 13,
37e49.
Sellers, E.M.,M.P., Roy, M.L., Sellers, E.A., 1979. Amphetamines. In: Lomax, P, S. E. e.
(Ed.), Modern Pharmacology-toxicology, Body Temperature: Regulation, Drug
Effects and Therapeutic Implications. Marcel Dekker, Inc., New York,
pp. 461e498.
Shram, M.J., Schoedel, K.A., Bartlett, C., Shazer, R.L., Anderson, C.M., Sellers, E.M.,
2011a. Evaluation of the abuse potential of lorcaserin, a serotonin 2C (5-HT2C)
receptor agonist, in recreational polydrug users. Clin. Pharmacol. Ther. 89,
683e692.
Shram, M.J., Sellers, E.M., Romach, M.K., 2011b. Oral ketamine as a positive control
in human abuse potential studies. Drug Alcohol Depend. 114, 185e193.
Shram, M., Levy-Cooperman, N., Chen, N., Mills, C., Bartlett, C., Setnik, B., van der
Graaf, P., Ratcliffe, S., Schoedel, K., 2012. Sensitivity and Performance of Derived
Parameters from Human Abuse Potential Studies. College on Problems of Drug
Dependence, Palm Springs, California.
Singh, J.B., Fedgchin, M., Daly, E., Xi, L., Melman, C., De Bruecker, G., Tadic, A.,
Sienaert, P., Wiegand, F., Manji, H., Drevets, W.C., Van Nueten, L., 2016. Intra-
venous esketamine in adult treatment-resistant depression: a double-blind,
double-randomization, placebo-controlled study. Biol. Psychiatry 80, 424e431.
Spiegel, D., 2016. Psilocybin-assisted psychotherapy for dying cancer patients -
aiding the final trip. J. Psychopharmacol. 30, 1215e1217.
Stein, D.J., Ipser, J.C., Seedat, S., 2006. Pharmacotherapy for post traumatic stress
disorder (PTSD). Cochrane Database Syst Rev Cd002795.
Strassman, R.J., 1996. Human psychopharmacology of N,N-dimethyltryptamine.
Behav. Brain Res. 73, 121e124.
Strassman, R.J., Qualls, C.R., Uhlenhuth, E.H., Kellner, R., 1994. Dose-response study
of N,N-dimethyltryptamine in humans. II. Subjective effects and preliminary
results of a new rating scale. Arch. Gen. Psychiatry 51, 98e108.
Studerus, E., Gamma, A., Vollenweider, F.X., 2010. Psychometric evaluation of the
altered states of consciousness rating scale (OAV). PLoS One 5, e12412.
Studerus, E., Kometer, M., Hasler, F., Vollenweider, F.X., 2011. Acute, subacute and
long-term subjective effects of psilocybin in healthy humans: a pooled analysis
of experimental studies. J. Psychopharmacol. 25, 1434e1452.
Studerus, E., Gamma, A., Kometer, M., Vollenweider, F.X., 2012. Prediction of psi-
locybin response in healthy volunteers. PLoS One 7, e30800.
Suwaki, H., Kalant, H., Higuchi, S., Crabbe, J.C., Ohkuma, S., Katsura, M.,
Yoshimura, M., Stewart, R.C., Li, T.K., Weiss, F., 2001. Recent research on alcohol
tolerance and dependence. Alcohol Clin. Exp. Res. 25, 189se196s.
Turton, S., Nutt, D.J., Carhart-Harris, R.L., 2014. A qualitative report on the subjective
experience of intravenous psilocybin administered in an FMRI environment.
Curr. Drug Abuse Rev. 7, 117e127.
Tyls, F., Palenicek, T., Horacek, J., 2014. Psilocybinesummary of knowledge and new
perspectives. Eur. Neuropsychopharmacol. 24, 342e356.
Tyndale, R.F., Li, Y., Li, N.Y., Messina, E., Miksys, S., Sellers, E.M., 1999. Character-
ization of cytochrome P-450 2D1 activity in rat brain: high-affinity kinetics for
dextromethorphan. Drug Metab. Dispos. 27, 924e930.
Vande Voort, J.L., Morgan, R.J., Kung, S., Rasmussen, K.G., Rico, J., Palmer, B.A.,
Schak, K.M., Tye, S.J., Ritter, M.J., Frye, M.A., Bobo, W.V., 2016. Continuation
phase intravenous ketamine in adults with treatment-resistant depression.
J. Affect Disord. 206, 300e304.
Vieira, A., Melo, C., Machado, J., Gabriel, J., 2017. Virtual reality exercise on a home-
based phase III cardiac rehabilitation program, effect on executive function,
quality of life and depression, anxiety and stress: a randomized controlled trial.
Disabil. Rehabil. Assist. Technol. 1e12.
Vortherms, T.A., Roth, B.L., 2006. Salvinorin A: from natural product to human
therapeutics. Mol. Interv. 6, 257e265.
White, S.R., Obradovic, T., Imel, K.M., Wheaton, M.J., 1996. The effects of methyl-
enedioxymethamphetamine (MDMA, "Ecstasy") on monoaminergic neuro-
transmission in the central nervous system. Prog. Neurobiol. 49, 455e479.
Wiederhold, B.K., Gao, K., Kong, L., Wiederhold, M.D., 2014a. Mobile devices as
adjunctive pain management tools. Cyberpsychol Behav. Soc. Netw. 17,
385e389.
Wiederhold, M.D., Gao, K., Wiederhold, B.K., 2014b. Clinical use of virtual reality
distraction system to reduce anxiety and pain in dental procedures. Cyberp-
sychol Behav. Soc. Netw. 17, 359e365.
Wilkinson, S.T., Sanacora, G., 2017. Considerations on the Off-Label Use of Ketamine
as a Treatment for Mood Disorders. JAMA.
Wilkinson, S.T., Toprak, M., Turner, M.S., Levine, S.P., Katz, R.B., Sanacora, G., 2017.
A survey of the clinical, off-label use of ketamine as a treatment for psychiatric
disorders. Am. J. Psychiatry 174, 695e696.
Winkelman, M., 2014. Psychedelics as medicines for substance abuse rehabilitation:
evaluating treatments with LSD, Peyote, Ibogaine and Ayahuasca. Curr. Drug
Abuse Rev. 7, 101e116.
Wright, G.E., Niehaus, D.J., Drogemoller, B.I., Koen, L., Gaedigk, A., Warnich, L., 2010.
Elucidation of CYP2D6 genetic diversity in a unique African population: im-
plications for the future application of pharmacogenetics in the Xhosa popu-
lation. Ann. Hum. Genet. 74, 340e350.
Xu, Y., Hackett, M., Carter, G., Loo, C., Galvez, V., Glozier, N., Glue, P., Lapidus, K.,
McGirr, A., Somogyi, A.A., Mitchell, P.B., Rodgers, A., 2016. Effects of low-dose
and very low-dose ketamine among patients with major depression: a sys-
tematic review and meta-analysis. Int. J. Neuropsychopharmacol. 19.
Yang, J., Jamei, M., Heydari, A., Yeo, K.R., de la Torre, R., Farre, M., Tucker, G.T.,
 Edward.M. Sellers et al. / Neuropharmacology xxx (2017) 1e19 19

Rostami-Hodjegan, A., 2006. Implications of mechanism-based inhibition of
CYP2D6 for the pharmacokinetics and toxicity of MDMA. J. Psychopharmacol.
20, 842e849.
Yazar-Klosinski, B.B., Mithoefer, M.C., 2017. Potential psychiatric uses for MDMA.
Clin. Pharmacol. Ther. 101, 194e196.
Zawertailo, L.A., Kaplan, H.L., Busto, U.E., Tyndale, R.F., Sellers, E.M., 1998.
Psychotropic effects of dextromethorphan are altered by the CYP2D6 poly-
morphism: a pilot study. J. Clin. Psychopharmacol. 18, 332e337.
Zawertailo, L.A., Tyndale, R.F., Busto, U., Sellers, E.M., 2010. Effect of metabolic
blockade on the psychoactive effects of dextromethorphan. Hum. Psycho-
pharmacol. 25, 71e79.

Please cite this article in press as: Sellers, E.M., et al., Studies with psychedelic drugs in human volunteers, Neuropharmacology (2017), https://
doi.org/10.1016/j.neuropharm.2017.11.029