the role of psychedelics in medicine: historical context
TRANSCRIPT
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The Role of Psychedelics in Medicine:
Historical Context and Current Clinical Applications
WHITE PAPER
April 20, 2021
John Schneider, PhD1
Bennet Zelner, PhD2
Karen Beltran1
1Avalon Health Economics, Morristown, NJ 2University of Maryland, College Park, MD
Corresponding Author:
John E. Schneider, PhD
Avalon Health Economics LLC
26 Washington St., 3rd Floor
Morristown, NJ 07960
Acknowledgements: The authors would like to thank Bob Jesse, Anny Ortiz, and Connor Feldman
for their valuable contributions, insights, and edits; and Dr. Bronner’s, the Nikean Foundation, the
Riverstyx Foundation, the Turnbull Family Foundation, and Usona Institute for their generous
financial support.
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1. INTRODUCTION
Psychedelics, also known as hallucinogens, entheogens, and psychotomimetics,1 are psychoactive
drugs that have been shown to alter consciousness and cognitive processes. Though psychedelic
plants and fungi were first discovered more than a few thousand years ago,2 the chemistry and
pharmacology of psychedelics were not investigated in the context of modern science until the
1950s.3 Even as biomedical research began to show these compounds’ potential promise in
treating various psychiatric conditions, sociopolitical opposition stemming from psychedelics’
illicit use by members of the 1960s and 70s counterculture slowed progress and hindered
widespread acceptance.4 The situation shift again in the 1990s and early 2000s, as rigorous new
medical research gave rise to an evidentiary foundation upon which the modern era of psychedelic
research would be based. This research has sparked renewed interest in the role of psychedelics in
clinical settings, where they may potentially treat a variety of psychiatric conditions.5
In this study, we conduct a comprehensive “meta-review” of the historical context and
development of clinical applications of psychedelics. The review focuses on two primary
questions. First, given the long history of psychedelics, how has research evolved, and how does
it inform psychedelics’ present-day clinical landscape? Second, how are psychedelics currently
being applied in clinical settings, and what are the origins of these applications? Both questions
have been addressed in existing literature to some extent, but with two important gaps. First,
despite the publication of several systematic literature reviews in recent years, there has not yet
existed a “meta-review” of these systematic reviews, especially one focused on clinical studies.
Second, existing studies generally do not tie together historical context and current applications.
The chief objective of this study is therefore not to replicate or update prior systematic reviews,
but rather to link together what are essentially two generations of thinking on psychedelics, a
“discovery” era and an emerging “application” era, while maintaining historical perspective. Such
an analysis helps to illuminate key issues that have surfaced in the recent public discourse on
psychedelics. These include the extent to which prior knowledge from both formal and informal
1 In this paper we have chosen to use the term widely used term “psychedelics,” though we note that several
prominent early researchers criticized the term for “etymologically unsound.” Refer to R.E. Schultes, A.
Hofmann, and C. Ratsch, Plants of the Gods: Their Sacred, Healing, and Hallucinogenic Powers
(Rochester, VT: Healing Arts Press, 1998). 2 F. J. Carod-Artal, "Hallucinogenic drugs in pre-Columbian Mesoamerican cultures," Neurologia 30, no.
1 (2015). 3 D. X. Freedman, "Effects of LSD-25 on brain serotonin," J Pharmacol Exp Ther 134 (1961); M. Rinkel,
"Psychedelic drugs," Am J Psychiatry 122, no. 12 (1966); L. Grinspoon and J. B. Bakalar, Psychedelic
Drugs Reconsidered (New York, NY: Basic Books, 1979). 4 A. A. Weech, Jr. and R. E. Bibb, "Toward a rational approach to psychedelics: the controversy over
popular use from a clinical viewpoint," Compr Psychiatry 11, no. 1 (1970). 5 R. L. Carhart-Harris and G. M. Goodwin, "The Therapeutic Potential of Psychedelic Drugs: Past, Present,
and Future," Neuropsychopharmacology 42, no. 11 (2017); T. Chi and J. A. Gold, "A review of emerging
therapeutic potential of psychedelic drugs in the treatment of psychiatric illnesses," J Neurol Sci 411 (2020);
M. W. Johnson et al., "Classic psychedelics: An integrative review of epidemiology, therapeutics, mystical
experience, and brain network function," Pharmacol Ther 197 (2019); S. Muttoni, M. Ardissino, and C.
John, "Classical psychedelics for the treatment of depression and anxiety: A systematic review," J Affect
Disord 258 (2019); D. E. Nichols, "Psychedelics," Pharmacol Rev 68, no. 2 (2016).
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sources has contributed to current scientific research and clinical practice, which may have
implications for the legal assignment of intellectual property (IP) rights; and the extent to which
the mainstream medical-therapeutic model of mental healthcare supports or limits psychedelics’
healing potential.
The review uses a “snowball” method, a qualitative approach in which (1) basic search terms are
used to identify an initial comprehensive list of sources; and (2) a review of those sources is
conducted to identify “leading” sources, generally defined as those which directly address the
research questions and are frequently cited by other sources.6 The main search engines used were
PubMed and Google. No time horizons were specified, but all sources had to include an abstract
and English language full text to be included.
The paper is organized as follows. The next section reviews general background on the basic types
of psychedelics and mechanisms of action. The remaining sections describe the review’s main
findings, beginning with the historical context of psychedelics and concluding with a review of
current clinical applications.
2. MECHANISMS
In this section we provide a brief review of psychedelics’ biochemical mechanisms of action,
which have been described at length elsewhere.7 We also discuss the perspective that, in contrast
to the effects of conventional psychiatric drugs, the psychological effects of psychedelics cannot
be fully understood in terms of biochemical mechanisms alone, and necessarily reflect contextual
and experiential influences.
Psychedelics are typically grouped into three broad categories based on their pharmacological
profiles and chemical structures: (1) “classic” psychedelics, (2) empathogens, and (3) other
psychedelics, including dissociative anesthetic agents and atypical hallucinogens.8 Classic
psychedelics (also referred to as serotonergic psychedelics) include mescaline, lysergic acid
6 S. Tenny et al., "Qualitative Study," in StatPearls (Treasure Island (FL): StatPearls Publishing LLC,
2020). 7 C. E. Canal, "Serotonergic Psychedelics: Experimental Approaches for Assessing Mechanisms of Action,"
Handb Exp Pharmacol 252 (2018); R. L. Carhart-Harris, "How do psychedelics work?," Curr Opin
Psychiatry 32, no. 1 (2019); R. L. Carhart-Harris et al., "Psychedelics and connectedness,"
Psychopharmacology (Berl) 235, no. 2 (2018); R. L. Carhart-Harris and D. J. Nutt, "Serotonin and brain
function: a tale of two receptors," J Psychopharmacol 31, no. 9 (2017); M. E. Liechti, "Modern Clinical
Research on LSD," Neuropsychopharmacology 42, no. 11 (2017); L. J. Mertens et al., "Therapeutic
mechanisms of psilocybin: Changes in amygdala and prefrontal functional connectivity during emotional
processing after psilocybin for treatment-resistant depression," J Psychopharmacol 34, no. 2 (2020); D. E.
Nichols, "Chemistry and Structure-Activity Relationships of Psychedelics," Curr Top Behav Neurosci 36
(2018); M. K. Madsen et al., "A single psilocybin dose is associated with long-term increased mindfulness,
preceded by a proportional change in neocortical 5-HT2A receptor binding," Eur Neuropsychopharmacol
33 (2020). 8 See generally Collin M. Reiff et al., "Psychedelics and Psychedelic-Assisted Psychotherapy," American
Journal of Psychiatry 177, no. 5 (2020). In this paper, we focus on classic psychedelics and empathogens
as these have been the focus of the vast majority of clinical research.
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diethylamide (LSD), psilocybin, N,N-Dimethyltryptamine (DMT), and ayahuasca (broadly
described as a decoction of plants containing DMT, harmala alkaloids, and other agents according
to local custom). Psychedelics share in common the stimulation of the serotonin 5-
hydroxytryptamine 2A (5-HT2A) receptor, which has been hypothesized to lead to an increase in
glutamate release in the prefrontal cortex.9 Research in this vein dates first to 1953, when Gaddum
revealed that LSD-25 antagonizes specific peripheral actions of the 5-hydroxytryptamine (5-HT)
receptor, and then hypothesized that a similar antagonism to actions of serotonin in the nervous
system produces altered state of consciousness.10 More recently, Carhart-Harris et al. used neuro-
imaging techniques to show that when visual cortex cerebral blood flow (CBF) increased, visual
cortex alpha power decreased, causing a strong correlation between expanded primary visual
cortex (V1) functional connectivity and visual hallucinations.11 The study demonstrated how
intrinsic brain activity affects the visual processing of a participant, explaining the hallucinatory
quality of LSD.
Empathogens, such as 3,4-Methylenedioxymethamphetamine (MDMA), are characterized by their
effects on the inhibition and release of serotonin and dopamine.12 Structurally, MDMA resembles
mescaline and amphetamine, though the dextrorotatory isomer of MDMA displays more activity
in the central nervous system.13 The biochemical effect of empathogens is caused by the release of
calcium-independent 5-HT, which leads to the expansion of 5-HT neurotransmission.14
Empathogens are known to produce euphoria and a sense of emotional connectedness and
openness to others, in part due to their impact on monoamine reuptake inhibition and release.15
Psychedelics’ novel biochemical mechanisms are associated with qualitatively different types of
participant experiences from those associated with conventional psychopharmacological agents.
These may include “an altered state of consciousness, closed-eyes imagery, changes in perception,
mood and affect, [and] a weakened sense of self or ego.”16 Growing evidence suggests that effects
such as these are not simply “side effects,” but may themselves contribute directly to clinical
outcomes. For example, Griffiths et al. reported that “psilocybin can occasion mystical-type
experiences having persisting positive effects on attitudes, mood, and behavior” among some
9 Ibid.; F. X. Vollenweider and M. Kometer, "The neurobiology of psychedelic drugs: implications for the
treatment of mood disorders," Nat Rev Neurosci 11, no. 9 (2010); J. W. Muschamp et al., "Lysergic acid
diethylamide and [-]-2,5-dimethoxy-4-methylamphetamine increase extracellular glutamate in rat
prefrontal cortex," Brain Res 1023, no. 1 (2004). 10 R. J. Boakes et al., "Antagonism of 5-hydroxytryptamine by LSD 25 in the central nervous system: a
possible neuronal basis for the actions of LSD 25," British journal of pharmacology 40, no. 2 (1970). 11 Robin L. Carhart-Harris et al., "Neural correlates of the LSD experience revealed by multimodal
neuroimaging," Proceedings of the National Academy of Sciences of the United States of America 113, no.
17 (2016). 12 Reiff et al. 13 Henry David Abraham, Una D Mccann, and George A Ricaurte, "Psychedelic drugs,"
Neuropsychopharmacology: the fifth generation of progress. (2002). 14 Ibid. 15 Brian Holoyda, "The Psychedelic Renaissance and Its Forensic Implications," Journal of the American
Academy of Psychiatry and the Law Online (2020). 16 Madsen et al.
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participants,17 and Watts et al. found that psilocybin alleviated depression in some recipients by
helping them move from “disconnection (from self, others, and world) to connection” and
“avoidance (of emotion) to acceptance.”18 Carhart-Harris et al. pointed directly to the nexus
between biochemical mechanisms and subjective cognitive experience, writing that “psychedelics
initiate a cascade of neurobiological changes that manifest at multiple scales and ultimately
culminate in the relaxation of high-level beliefs.”19
The likelihood that psychedelics “may work via paradigmatically novel means”20 relative to
conventional psychopharmacological and psychotherapeutic treatments has implications for how
these substances might be administered to maximize therapeutic benefit. It has been recognized
since at least the 1960s that “set and setting” – the mindset of the individual entering a psychedelic
experience (set) and the environment in which the experience takes place (setting)21– have a
profound influence on the nature and outcome of psychedelic experiences. In the late 1990s Eisner
expanded this idea into the concept of the “matrix,” which includes consideration of the
“environment (1) from which an individual comes, (2) in which the individual lives during the
time of the sessions, and (3) to which the individual returns after successful therapy – the everyday
living space.”22 More recent research has developed specific psychotherapeutic techniques for use
with patients undergoing treatment with psychedelics, in the form of Watts et al.’s ACE (Accept,
Connect, Embody) model.23
3. EARLY EVIDENCE
Few chemical compounds, if any, have as rich and deep a history as psychedelics, whose use in
the form of plant and fungal hallucinogens likely dates to pre-historic times. In some cultures,
shamans would conduct prayer or healing ceremonies by performing rituals featuring the use of
17 See generally R. R. Griffiths et al., "Psilocybin occasioned mystical-type experiences: immediate and
persisting dose-related effects," Psychopharmacology (Berl) 218, no. 4 (2011). Also see M. B. Bowers, Jr.
and D. X. Freedman, ""Psychedelic" experiences in acute psychoses," Arch Gen Psychiatry 15, no. 3
(1966); T. M. Carbonaro et al., "Survey study of challenging experiences after ingesting psilocybin
mushrooms: Acute and enduring positive and negative consequences," J Psychopharmacol 30, no. 12
(2016); R. R. Griffiths et al., "Psilocybin can occasion mystical-type experiences having substantial and
sustained personal meaning and spiritual significance," Psychopharmacology (Berl) 187, no. 3 (2006); I.
Hartogsohn, American Trip: Set, Setting, and Psychedelic Experience in the Twentieth Century
(Cambridge, Massachusetts: The MIT Press, 2020); M. M. Nour and R. L. Carhart-Harris, "Psychedelics
and the science of self-experience," Br J Psychiatry 210, no. 3 (2017). 18 Rosalind Watts et al., "Patients’ Accounts of Increased “Connectedness” and “Acceptance” After
Psilocybin for Treatment-Resistant Depression," Journal of Humanistic Psychology 57, no. 5 (2017). Also
see R. L. Carhart-Harris et al., "Psychedelics and connectedness," Psychopharmacology 235, no. 2 (2018). 19 Carhart-Harris. 20 Watts et al. 21 T. Leary, R. Metzner, and R. Alpert, The Psychedelic Experience (New York, NY: Citadel Press Books,
1964); Hartogsohn. 22 B. Eisner, "Set, setting, and matrix," J Psychoactive Drugs 29, no. 2 (1997). 23 Rosalind Watts and Jason B. Luoma, "The use of the psychological flexibility model to support
psychedelic assisted therapy," Journal of Contextual Behavioral Science 15 (2020).
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psychoactive plant medicines.24 It has even been argued that “the whole idea of the deity could
have arisen as a result of the other worldly effects of these agents,” and that hallucinogenic plants
were considered to be “gifts from the gods.”25
Psychedelics were likely used in the Vedic religion in the mountains of Afghanistan as early as
1600 B.C. Mushrooms were used in the Yucatan before the time of the Mayans (c. 900 A.D.-1300
A.D.), by the Toltec and Nahua predecessors of the Aztecs.26 Some evidence, however – including
mushroom shaped-sculptures and etchings – suggests an even deeper history of the use of
psychedelics in religion and medicine, perhaps dating as far back as 5000 B.C.27
As an example, more than 3,500 years ago, Soma, an ancient Indian god, occupied an exalted
position in the Aryans’ magico-religious ceremonies in the Indus Valley. The Soma cult devoted
many holy hymns to a sacred narcotic that was later believed to be based on a fungus called
Amanita muscaria (“The Fly Agaric”). The Soma’s sacred fungus is known to be one of the oldest
hallucinogens used.28 Similarly, in Aztec rituals, diviners were said to achieve inspiration during
spectacular ceremonies featuring the ingestion of hallucinogenic mushrooms, which they called
teonanacatl, or “god’s flesh.”29 Some of these wisdom traditions, such as the Mexican Mazatec
Indians’ ritualistic use of the hallucinogenic plant salvia divinorum, have endured for centuries.30
4. SCIENTIFIC DISCOVERY
The earliest formal exploration of the “psychotomimetic paradigm” was described by Moreau in
1845, regarding hashish and the deliriants henbane, belladonna, and datura.31 This was followed
decades later in 1898 when Arthur Heffter isolated mescaline from the peyote cactus of Mexican
origins.32 But the most important scientific advancement in psychedelics came nearly four decades
after Heffter, when in 1938 the Swiss chemist Albert Hofmann created LSD-25 at the Sandoz
laboratories in Switzerland when testing alkaloids from rye ergot fungus.33 After resynthesizing
LSD-25 in 1943, Hofmann accidentally ingested a minuscule amount, and the experience that
24 I. Byock, "Taking Psychedelics Seriously," J Palliat Med 21, no. 4 (2018). 25 Schultes, Hofmann, and Ratsch. 26 Grinspoon and Bakalar. 27 Johnson et al. Brian P. Akers et al., "A Prehistoric Mural in Spain Depicting Neurotropic Psilocybe
Mushrooms?," Economic Botany 65, no. 2 (2011). Grinspoon and Bakalar. 28 Schultes, Hofmann, and Ratsch. 29 Frank Barron, Murray E. Jarvik, and Sterling Bunnell, "The Hallucinogenic Drugs," Scientific American
210, no. 4 (1964). 30 I. Casselman et al., "From local to global-fifty years of research on Salvia divinorum," J Ethnopharmacol
151, no. 2 (2014); P. Dalgarno, "Subjective effects of Salvia divinorum," J Psychoactive Drugs 39, no. 2
(2007); J. Listos, A. Merska, and S. Fidecka, "Pharmacological activity of salvinorin A, the major
component of Salvia divinorum," Pharmacol Rep 63, no. 6 (2011). 31 Hartogsohn. 32 B. K. Cassels and P. Sáez-Briones, "Dark Classics in Chemical Neuroscience: Mescaline," ACS Chem
Neurosci 9, no. 10 (2018). 33 D. E. Nichols, "Dark Classics in Chemical Neuroscience: Lysergic Acid Diethylamide (LSD)," ibid.; A.
Hofmann, LSD: My Problem Child (Santa Cruz, CA: Multidisciplinary Association for Psychedelic Studies
(MAPS), 2009).
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followed helped him understand the potency and psychoactive properties of the compound. In
1947, to promote further research, Sandoz laboratories made LSD-25 (under the name “Delysid”)
available to researchers and clinicians, which in turn helped initiate animal testing and
experimental human use in the in the 1950s.34
A decade after Albert Hofmann’s synthesis of LSD in the laboratory, the therapeutic application
of psychedelics was explored in 1953 by A.M. Hubbard and continued by Humphry Osmond.35
Max Rinkel’s interest in experimental production of psychosis is also thought to be an important
milestone in medical research on psychedelics in the early 1950s.36 In 1958, Hofmann identified
psilocybin as a psychoactive compound in Psilocybe mushrooms, which was then synthesized and
made available to researchers in 1959 by Sandoz laboratories as “Indocybin.”37 As research on
psychedelics progressed, the underlying conceptual assumption of the application of psychedelics
to mental health was that “if one traumatic event can shape a life, one therapeutic event can reshape
it.”38
During the 1950s and 1960s, and into the 1970s, more than 1,000 clinical papers were published
on the therapeutic uses of psychedelics in a variety of mental health applications (Figure 1),
resulting in the emergence of the field termed “experimental psychiatry,” mainly pertaining to
research on the properties and effects of experimentally induced states of psychosis.
34 E. J. Kyzar et al., "Psychedelic Drugs in Biomedicine," Trends Pharmacol Sci 38, no. 11 (2017). 35 Grinspoon and Bakalar. 36 Hartogsohn; Rinkel. 37 H. A. Geiger, M. G. Wurst, and R. N. Daniels, "DARK Classics in Chemical Neuroscience: Psilocybin,"
ACS Chem Neurosci 9, no. 10 (2018). 38 Grinspoon and Bakalar. p.195
0
100
200
300
400
500
600
700
800
900
1945 1950 1955 1960 1965 1970 1975 1980 1985 1990 1995 2000 2005 2010 2015 2020
Figure 1. Number of Publications Per Year with Keyword "Psychedelic" Indexed in PubMed: 1945-2020
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The 1950s through the 1970s later became known as the “golden period” of experimental
psychiatry psychopharmacology, and marked the beginning of what some called the
“pharmacology of consciousness.”39 Some of the most important contributions of this time period
were in gaining a more complete understanding of the biochemical and neurological properties of
psychedelics,40 particularly their interactions with the brain's serotonin system.41 During this same
time period, experiences with psychedelic drugs also “jumped the laboratory walls” 42 through the
work of Harvard research psychologist Timothy Leary and others, setting the stage for a
sociopolitical backlash.
5. SOCIOPOLITICAL BACKLASH
Despite the rapid and promising advances in psychedelic research from the 1950s through the
1970s, psychedelic research suffered important setbacks toward the end of this period. In contrast
to other promising medical compounds that fade away after underperforming in early clinical
studies, the setbacks suffered by psychedelics were not generally associated with their performance
in laboratory and clinical settings.43 Rather, they were generally attributed to three factors:44 (1)
rising recreational use (and misuse) of LSD, which was linked by the mainstream media to a
counterculture narrative perceived as threatening by a large segment of the population;45 (2) lack
of understanding by the mainstream medical establishment of the value of psychedelics in medical
applications; and (3) difficulties in designing randomized controlled trials (RCTs) to study clinical
outcomes with an appropriate control substance (i.e., an active placebo).
Sandoz laboratories ended its distribution of LSD in 1966.46 Four years later, the United States
Congress passed the Controlled Substances Act of 1970, which placed most psychedelic drugs on
39 S Grof, "Foreword in LSD: My Problem Child, by Albert Hofmann," in LSD: My Problem Child (Santa
Cruz, CA: Multidisciplinary Association for Psychedelic Studies (MAPS), 2005). 40 See generally A. Hofmann, "Psychotomimetic drugs; chemical and pharmacological aspects," Acta
Physiol Pharmacol Neerl 8 (1959); A. T. Shulgin, "Psychotomimetic agents related to mescaline,"
Experientia 19 (1963); N. J. Giarman and D. X. Freedman, "Biochemical Aspects of the Actions of
Psychotomemetic Drugs," Pharmacol Rev 17 (1965); D. X. Freedman, "The psychopharmacology of
hallucinogenic agents," Annu Rev Med 20 (1969); A. T. Shulgin, "Mescaline: the chemistry and
pharmacology of its analogs," Lloydia 36, no. 1 (1973); "Chemistry of phenethylamines related to
mescaline," J Psychedelic Drugs 11, no. 1-2 (1979). 41 See generally P. A. Shore, S. L. Silver, and B. B. Brodie, "Interaction of serotonin and lysergic acid
diethylamide (LSD) in the central nervous system," Experientia 11, no. 7 (1955); E. Shaw and D. W.
Woolley, "Some serotoninlike activities of lysergic acid diethylamide," Science 124, no. 3212 (1956);
Freedman, "Effects of LSD-25 on brain serotonin." 42 M. Pollan, How to Change Your Mind (New York, NY: Penguin Press, 2018). 43 Grof. 44 S. J. Belouin and J. E. Henningfield, "Psychedelics: Where we are now, why we got here, what we must
do," Neuropharmacology 142 (2018); Grof. 45 For example, Richard Nixon in 1971 described Timothy Leary as “the most dangerous man in America.”
See Pollan. 46 E. Dyck, "Flashback: psychiatric experimentation with LSD in historical perspective," Can J Psychiatry
50, no. 7 (2005).
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“Schedule I,”47 signifying that they had a high potential for abuse and no legitimate medical use,
and therefore could not be prescribed, dispensed, or administered.48 These restrictions were
buttressed in 1971 by the United Nations Convention on Psychotropic Substances, which
implemented restrictions on importing and exporting, and created additional rules limiting use to
specific scientific and medicinal purposes.49 The overall effects of these restrictions on scientific
research can be seen in Figure 1, which shows a precipitous decline in the volume of published
material on psychedelics from the early 1970s through the 1980s.
6. SCIENTIFIC PERSISTENCE
Despite the prohibition on recreational and medical use of psychedelics, biomedical research
persisted at a rate of over 300 publications per year from the 1970s to the 1990s, mainly at private
research organizations and universities.50 The continuation of psychedelic research during this
period resulted in several important contributions on biomedical properties and mechanisms of
action, in addition to findings on potential therapeutic applications in a variety of mental health
conditions, including depression, anxiety, and addiction.51
Exploring applications in depression, Grinspoon and Bakalar in 1986 reviewed some of the
existing case studies of the use of psychedelics to treat depression (primarily as an adjunct to
psychotherapy), concluding that the research from the 1970s and 1980s had been very promising.52
One of the earliest controlled studies of psychedelic-like treatment of depression came in 1999,
when Berman et al. conducted a double-blinded study of seven subjects with Major Depressive
Disorder (MDD).53 Relying on a randomized, double-blind study design, patients underwent two
days of treatment, separated by a week. Four randomly chosen participants received 0.5mg/kg of
intravenous ketamine hydrochloride, and the remaining three received a placebo saline solution.
47 Kyzar et al. 48 Michael Gabay, "The federal controlled substances act: schedules and pharmacy registration," Hospital
pharmacy 48, no. 6 (2013). 49 David R. Bewley-Taylor, "Challenging the UN drug control conventions: problems and possibilities,"
International Journal of Drug Policy 14, no. 2 (2003). 50 Grinspoon and Bakalar; Pollan. 51 See generally D. E. Nichols and A. T. Shulgin, "Sulfur analogs of psychotomimetic amines," J Pharm
Sci 65, no. 10 (1976); A. T. Shulgin, "Profiles of psychedelic drugs," J Psychedelic Drugs 12, no. 2 (1980);
D. X. Freedman, "Hallucinogenic drug research--if so, so what? Symposium summary and commentary,"
Pharmacol Biochem Behav 24, no. 2 (1986); L. Grinspoon and J. B. Bakalar, "Can drugs be used to enhance
the psychotherapeutic process?," Am J Psychother 40, no. 3 (1986); T. J. Riedlinger and J. E. Riedlinger,
"Psychedelic and entactogenic drugs in the treatment of depression," J Psychoactive Drugs 26, no. 1 (1994);
F. X. Vollenweider, "Advances and pathophysiological models of hallucinogenic drug actions in humans:
a preamble to schizophrenia research," Pharmacopsychiatry 31 Suppl 2 (1998); F. X. Vollenweider et al.,
"Psilocybin induces schizophrenia-like psychosis in humans via a serotonin-2 agonist action," Neuroreport
9, no. 17 (1998). 52 Grinspoon and Bakalar, "Can drugs be used to enhance the psychotherapeutic process?." 53 R. M. Berman et al., "Antidepressant effects of ketamine in depressed patients," Biol Psychiatry 47, no.
4 (2000).
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After three days of the treatment, the Hamilton Depression Rating Scale (HDRS, or HAM-D)54
scores decreased by 50% or more in the experimental group versus the control group.
The period of scientific persistence also included important research on the use of psychedelics to
treat anxiety, particularly that which is attributable to life-threatening illness.55 For example, Grof
et al. conducted study of 60 cancer patients, including a treatment group (administered 200-500µg
of LSD) and a control group (administered 60-105mg of dipropyltryptamine).56 Post-treatment
results showed that most patients experienced either substantial (26%) or moderate (42%)
improvement in depression and anxiety in the treatment group.
During this time research on the use of psychedelics to treat addiction also gained a foothold. For
example, in 1966 Smart et al. studied 30 participants in an inpatient alcohol treatment program, all
of whom underwent psychotherapy sessions prior to receiving drugs.57 Participants were split into
three groups of 10 each, the first of which received 800µg of LSD, the second of which received
60mg of ephedrine sulfate, and the third of which were not given any drugs. During the three-hour
drug treatment sessions, patients were accompanied by a doctor and nurse, and were asked a wide
range of questions. The LSD group experienced a 33.7% increase in abstinence, compared to
31.5% in the ephedrine group and 19.6% in the no-drug group.
7. CULTURAL RESURGENCE
The resurgence of psychedelic research began in the second half of the 1990s as the cultural imprint
of the Leary era faded, and the global rave and festival culture embraced the use of psychedelics
through the “psytrance” movement. In Silicon Valley, the popularization of the magazines Wired
and Mondo 2000 brought some legitimacy to what was termed the “cyberdelic” movement, and
also revived enthusiasm for the creative potential of micro-dosed psychedelic use.58 Fueled by
modern media and the internet, renewed enthusiasm for the potential of psychedelics spilled over
into the scientific community, reinvigorating research.59 In How to Change Your Mind, author
Michael Pollan attributed the resurgence to the persistent work of Roland Griffiths, Bob Jesse,
Rick Doblin and Bill Richards, and in particular Griffiths’ 2006 paper reporting on an RCT that
showed sustained mental health benefits associated with psilocybin.60
54 Rachel Sharp, "The Hamilton Rating Scale for Depression," Occupational Medicine 65, no. 4 (2015). 55 See generally W. N. Pahnke et al., "LSD-assisted psychotherapy with terminal cancer patients," Curr
Psychiatr Ther 9 (1969). 56 S. Grof et al., "LSD-Assisted Psychotherapy in Patients with Terminal Cancer," International
Pharmacopsychiatry 8 (1973). 57 Reginald G. Smart et al., "A Controlled Study of Lysergide in the Treatment of Alcoholism. I. The Effects
on Drinking Behavior," Quarterly Journal of Studies on Alcohol 27, no. 3 (1966). 58 Micro-dosing typically refers to roughly one-tenth of the normal pharmaceutical dose, as imprecise as
the latter is. See generally I. Hartogsohn, American Trip: Set, Setting, and Psychedelic Experience in the
Twenteith Century (Cambridge, Massachusetts: The MIT Press, 2020). 59 Charlotte Walsh, "Drugs, the Internet and Change," Journal of Psychoactive Drugs 43, no. 1 (2011). 60 Griffiths et al.
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A decade later, the medicinal value of psychedelics began to receive tacit endorsements from some
unlikely but influential sources.61 For example, a recent Netflix series chronicled the experiences
of individuals employed by actress Gwyneth Paltrow’s Goop Lab company on a retreat featuring
psilocybin treatments, where one employee revealed she felt she had “completed five years of
therapy in five hours.”62 Other recent documentaries, such as Have a Good Trip: Adventures in
Psychedelics, The Mind, Explained, and Fantastic Fungi have explored psychedelics from a social
and culture historical perspective, while at the same emphasizing the potential of these drugs in
treating a variety of mental health conditions.63 In addition to documentaries, an increasing amount
of detailed information on psychedelics has become available on a variety of websites, such as
Erowid, an online resource for psychedelic drug users, therapists, and other experts.64
In sum, the historical trajectory of psychedelics is somewhat unique from the perspective of
biomedical research. The era of scientific discovery was filled with promise, and Hofmann’s
captivating “discovery narrative” was befitting of the enthusiasm surrounding psychedelics’
potential. But the harshness of the backlash, while not enough to completely derail psychedelic
research, was certainly enough to impede its progress. The persistence of a handful of dedicated
researchers maintained a place for psychedelics in mental health treatment research long enough
for the turmoil of the 1960s to fade, allowing these substances once again to be considered a serious
alternative to existing treatments, many of which have failed to produce promised results.65
8. CURRENT APPLICATIONS
Resurgence of interest in psychedelics has resulted in what is now a rich and rapidly developing
clinical research agenda. In the past two decades, numerous studies have demonstrated clinical
effectiveness of psychedelics in the treatment of depression (MDD and Treatment Resistant
Depression [TRD]), anxiety (e.g., cancer-related psychiatric distress/anxiety disorders), addiction
(alcohol dependence and smoking cessation), and post-traumatic stress disorder (PTSD).66 In
recent years, this research has been extended to other areas, including obsessive-compulsive
disorder (OCD) and management of chronic pain.67 Between 1995 and 2010, the annual number
61 K. Shapiro, "Netflix And Trip: Take A Psychedelic Adventure In This Star-Studded Documentary," (New
York, NY2020). 62 J. Naftulin, "Gwyneth Paltrow sent her employees to take psychedelic mushrooms in Jamaica. One staffer
said she felt like she'd undergone 5 years of therapy.," (New York, NY2020). 63 Shapiro. 64 See generally http://www.erowid.org 65 David Nutt and Robin Carhart-Harris, "The Current Status of Psychedelics in Psychiatry," JAMA
Psychiatry (2020); P. Cuijpers, A. Stringaris, and M. Wolpert, "Treatment outcomes for depression:
challenges and opportunities," Lancet Psychiatry 7, no. 11 (2020). 66 Tingying Chi and Jessica A. Gold, "A review of emerging therapeutic potential of psychedelic drugs in
the treatment of psychiatric illnesses," Journal of the Neurological Sciences 411 (2020). D. E. Nichols, M.
W. Johnson, and C. D. Nichols, "Psychedelics as Medicines: An Emerging New Paradigm," Clin
Pharmacol Ther 101, no. 2 (2017). 67 P. L. Delgado and F. A. Moreno, "Hallucinogens, serotonin and obsessive-compulsive disorder," J
Psychoactive Drugs 30, no. 4 (1998); PhD Lugo-Radillo A Md and Jl Md Cortes-Lopez, "Long-term
Amelioration of OCD Symptoms in a Patient with Chronic Consumption of Psilocybin-containing
Mushrooms," ibid. (2020); J. A. Wilcox, "Psilocybin and Obsessive Compulsive Disorder," ibid.46, no. 5
Page 12 of 22
of scientific publications on psychedelics more than doubled, from about 350 to over 700 per year
until the COVID-19 pandemic in 2020 (Figure 1).68 Many of the studies published in this era were
more robust versions of the smaller case studies that characterized earlier stages of clinical
research. Several systematic reviews and meta-analyses summarizing the main findings of these
studies have also been conducted. In this section, we briefly review this work, focusing on the
treatment of depression, anxiety, addiction, and PTSD.
Depression
In recent years there have been 11 published systematic reviews and meta-analyses focused on the
use of psychedelics in the treatment of depressive disorders, mainly MDD and TRD.69 These
reviews shared similar selection criteria, with the main inclusion criteria being RCT study design
and treatments mostly consisting of various doses of LSD, psilocybin, or ayahuasca relative to a
placebo. Results of these systematic reviews have been remarkably consistent, showing sustained
positive effects of psychedelics as measured by a variety of commonly applied outcomes measures.
In addition, meta-analyses by Luoma et al. and Romeo et al. found average effect sizes larger than
those typically reported in studies of pharmacological and psychotherapy interventions. These
findings were confirmed in a recent meta-analysis by Galvão-Coelho et al., which reviewed data
from 12 RCT studies of the use of psychedelics (psilocybin, LSD, and ayahuasca) in treatment of
depression. The results mirrored those of other similar reviews, finding moderate significant effect
sizes in favor of psychedelics both short-term and long-term.
(2014); J. P. Castellanos et al., "Chronic pain and psychedelics: a review and proposed mechanism of
action," Reg Anesth Pain Med 45, no. 7 (2020). 68 The COVID-19 pandemic resulted in a significant slowdown in clinical studies globally, due in part to
the restrictions associated with general lockdowns, but also reluctance on the part of study subjects to
interact with health providers for non-life-threatening health care services. See generally F. S. E. Ebeid,
"COVID-19 effect on clinical research: Single-site risk management experience," Perspect Clin Res 11, no.
3 (2020). 69 K. A. A. Andersen et al., "Therapeutic effects of classic serotonergic psychedelics: A systematic review
of modern-era clinical studies," Acta Psychiatr Scand (2020); J. J. Breeksema et al., "Psychedelic
Treatments for Psychiatric Disorders: A Systematic Review and Thematic Synthesis of Patient Experiences
in Qualitative Studies," CNS Drugs 34, no. 9 (2020); R. G. Dos Santos et al., "Efficacy, tolerability, and
safety of serotonergic psychedelics for the management of mood, anxiety, and substance-use disorders: a
systematic review of systematic reviews," Expert Rev Clin Pharmacol 11, no. 9 (2018); J. J. Fuentes et al.,
"Therapeutic Use of LSD in Psychiatry: A Systematic Review of Randomized-Controlled Clinical Trials,"
Front Psychiatry 10 (2019); J. B. Luoma et al., "A Meta-Analysis of Placebo-Controlled Trials of
Psychedelic-Assisted Therapy," J Psychoactive Drugs (2020); Muttoni, Ardissino, and John; S. Reiche et
al., "Serotonergic hallucinogens in the treatment of anxiety and depression in patients suffering from a life-
threatening disease: A systematic review," Prog Neuropsychopharmacol Biol Psychiatry 81 (2018); B.
Romeo et al., "Efficacy of psychedelic treatments on depressive symptoms: A meta-analysis," J
Psychopharmacol (2020); J. J. Rucker et al., "Psychedelics in the treatment of unipolar mood disorders: a
systematic review," ibid.30, no. 12 (2016); A. Trope et al., "Psychedelic-Assisted Group Therapy: A
Systematic Review," J Psychoactive Drugs 51, no. 2 (2019); N. L. Galvão-Coelho et al., "Classic
serotonergic psychedelics for mood and depressive symptoms: a meta-analysis of mood disorder patients
and healthy participants," Psychopharmacology (Berl) 238, no. 2 (2021).
Page 13 of 22
Results on the clinical utility of psychedelics in treating depression have also been found to be
robust to patient-reported outcomes and clinician-judged improvement. For example, Rucker et al.
found that of 423 individuals in 19 studies, 79% showed clinician-judged improvement after
treatment with psychedelics.70 In addition, none of the reviews found evidence of significant
adverse events associated with psychedelic treatment for depression, and all reviews consistently
found robust evidence of both short-term and long-term reductions in psychiatric
symptomatology.71
Anxiety
Seven of the reviews covering depression also included anxiety. They found consistent evidence
of the efficacy of psychedelics in the treatment of anxiety, primarily in the context of cancer and
other life-threatening diseases. For example, Griffiths et al. conducted a double-blind study of
depression and anxiety in 51 cancer patients in a carefully constructed therapeutic context.72 Study
participants received either a low dose of oral psilocybin (1-3mg/kg) in the first session and a
higher dose (22-30mg/70kg) in a second session about five weeks (or the same dosages but in
reverse order). Five weeks after the first session, 92% of the participants in the group that had
received the higher dose first demonstrated a more than 50% decrease relative to baseline on the
GRID Hamilton Depression Rating Scale (GRID-HAMD), while the other group exhibited a 32%
treatment response rate. At six-month follow-up, 80% of participants continued to show
improvement in depressed moods and anxiety.
Addiction
Research on the use of psychedelics to treat addiction – especially alcoholism – dates to the
1960s.73 More recently, five systematic reviews have assessed the results of clinical studies of the
use of psychedelics to treat addiction.74 In a recent systematic review and meta-analysis, Krebs
and Johansen reviewed six randomized trials on psychedelics to treat alcoholism, representing 536
inpatient alcoholic volunteers across the six studies. A total of 325 individuals were randomly
chosen to receive a single high dose of LSD treatment. Overall, 59% demonstrated improved
70 Rucker et al. 71 Also see J. S. Aday et al., "Long-term effects of psychedelic drugs: A systematic review," Neurosci
Biobehav Rev 113 (2020). 72 R. R. Griffiths et al., "Psilocybin produces substantial and sustained decreases in depression and anxiety
in patients with life-threatening cancer: A randomized double-blind trial," J Psychopharmacol 30, no. 12
(2016). 73 See generally C. M. Smith, "A new adjunct to the treatment of alcoholism: the hallucinogenic drugs," Q
J Stud Alcohol 19, no. 3 (1958); R. G. Smart et al., "A controlled study of lysergide in the treatment of
alcoholism. 1. The effects on drinking behavior," ibid.27 (1966); A. Ludwig et al., "A clinical study of LSD
treatment in alcoholism," Am J Psychiatry 126, no. 1 (1969); R. Denson and D. Sydiaha, "A controlled
study of LSD treatment in alcoholism and neurosis," Br J Psychiatry 116, no. 533 (1970); L. A. Faillace,
A. Vourlekis, and S. Szara, "Hallucinogenic drugs in the treatment of alcoholism: a two-year follow-up,"
Compr Psychiatry 11, no. 1 (1970); F. S. Abuzzahab, Sr. and B. J. Anderson, "A review of LSD treatment
in alcoholism," Int Pharmacopsychiatry 6, no. 4 (1971). 74 Andersen et al; Breeksema et al; Dos Santos et al; Fuentes et al; T. S. Krebs and PØ Johansen, "Lysergic
acid diethylamide (LSD) for alcoholism: meta-analysis of randomized controlled trials," J
Psychopharmacol 26, no. 7 (2012).
Page 14 of 22
effects by the first follow-up, resulting in a 1.96 odds ratio for improvement. Though the literature
is somewhat less developed, addiction research with psychedelics has also been applied to smoking
cessation. For example, in 2014 Johnson et al. reported on an open-label pilot study of psilocybin
in the treatment of tobacco addiction.75 A total of 15 nicotine-dependent smokers participated in
the 15-week study. Psilocybin was administered at weeks 5, 7, and 13, of which the first session
included a 20mg/70kg moderate dose of psilocybin, and the other two sessions having a high dose
of 30mg/70kg. Of the 15 participants, 12 completed all three psilocybin sessions; of these, 80%
remained abstinent from smoking at 6-month follow-up. After 12-month follow-up, 67% remained
abstinent, and after 2.5 years the abstinence rate had fallen only to 60%.
PTSD
Finally, PTSD has also been a focus of psychedelic treatment, with four recent reviews assessing
clinical studies to date.76 For example, Varker et al. reviewed nine clinical studies, five with
ketamine and four with MDMA, concluding that the MDMA evidence on PTSD was moderate but
consistent. Important contributions to this literature were made by Mithoefer et al. In a 2011 study,
the authors conducted a double-blind randomized study of 20 PTSD patients, 12 of whom received
125mg of MDMA with psychotherapy and the other eight of which received placebos along with
psychotherapy.77 Participants were also given an optional dose of 62.5mg of MDMA 2-2.5 hours
later, depending on their response to the first dose. Upon treatment, the MDMA group
demonstrated a significantly greater improvement in the Clinician-Administered PTSD Scale
(CAPS). In the MDMA group, a positive response was observed in 83.3% of the participants.
Mithoefer et al. more recently conducted a randomized, double-blind study of MDMA-assisted
psychotherapy for PTSD in 26 military veterans and first responders.78 Seven participants received
75mg of MDMA and 12 participants received 125mg of MDMA. The control group consisted of
seven patients who were administered 30mg of MDMA. Based on their CAPS-IV scores after
treatment, the groups that were given 75mg and 125 mg demonstrated more significant decreases
in PTSD symptoms than the control group. In just one month after treatment, the mean change in
CAPS-IV from baseline was -58.3 for the 75mg group and -44.3 for the 125mg group. At the 12-
month follow up, all treatment groups had maintained gains.
75 M. W. Johnson et al., "Pilot study of the 5-HT2AR agonist psilocybin in the treatment of tobacco
addiction," ibid.28, no. 11 (2014). 76 Andersen et al; Breeksema et al; Fuentes et al; Luoma et al; T. Varker et al., "Efficacy of Psychoactive
Drugs for the Treatment of Posttraumatic Stress Disorder: A Systematic Review of MDMA, Ketamine,
LSD and Psilocybin," Journal of Psychoactive Drugs (2020). 77 M. C. Mithoefer et al., "The safety and efficacy of {+/-}3,4-methylenedioxymethamphetamine-assisted
psychotherapy in subjects with chronic, treatment-resistant posttraumatic stress disorder: the first
randomized controlled pilot study," J Psychopharmacol 25, no. 4 (2011). 78 Michael C. Mithoefer et al., "3,4-methylenedioxymethamphetamine (MDMA)-assisted psychotherapy
for post-traumatic stress disorder in military veterans, firefighters, and police officers: a randomised,
double-blind, dose-response, phase 2 clinical trial," The Lancet Psychiatry 5, no. 6 (2018).
Page 15 of 22
9. CONCLUSIONS
In this paper we have described the historical trajectory of psychedelics, from their millennia of
use in indigenous societies and wisdom traditions, to the frenetic period of scientific discovery in
the mid-20th Century followed by sociopolitical backlash, to the resurgence of scientific research
in the past two decades. While the richness of the history and current uses of psychedelics in mental
health suggest several interesting insights and conclusions, there are three that we wish to
emphasize.
First, psychedelics have an amazingly long history of medicinal and other beneficial uses. Unlike
many pharmaceutical compounds, psychedelics (by whatever name) were first discovered by
individuals with no formal training. Organic patterns of use and recorded outcomes over the
centuries offer insights unlike those that any bench science or clinical trial would likely be able to
offer. Albert Hofmann’s experience in the laboratory with LSD was indeed a discovery in the
modern sense, but a version of this discovery had taken place many times before, outside of the
laboratory and in astoundingly diverse cultures and settings. As recorded history moved from the
walls of caves to paper and then the digital world, the human experience with psychedelics has
told a remarkably consistent story. This story is compelling enough to have sustained the curiosity
of scientists who understood psychedelics’ potential even in the face of a multipronged backlash.
The fact that psychedelics sustained such keen interest over such a long period testifies to their
great promise. Moreover, because the large knowledge base accumulated throughout this history
necessarily informs current investigations and practices, it should be considered in current legal
and policy debates concerning psychedelics, such as those over the role of IP.
Second, the resurgence of psychedelic research in the past two decades has already generated a
large body of work that consistently points to the benefits of psychedelics in treating a variety of
mental health conditions. The findings from recently published systematic reviews and meta-
analyses of rigorously designed clinical research have added robust support to the earlier efficacy
findings. While this research needs to continue, especially with more controlled studies featuring
larger numbers of participants, those that have been published to date show clear benefits
associated with psychedelic-assisted treatment. These benefits are remarkably consistent with the
results of the smaller studies conducted in the 1960s and 1970s. Psychedelics may especially offer
hope to patients who fail to adequately respond to existing psychopharmacological treatments.
Finally, because psychedelics appear to operate through fundamentally different mechanisms from
those of conventional psychopharmacological and psychotherapeutic treatments, it is possible that
their clinical use will rise to a new paradigm for understanding and producing mental health. There
is clearly room for a new paradigm in mental health treatments, as existing treatments have
generally struggled to rise above 50% effectiveness. Early results from rigorous clinical research
on psychedelics suggest a markedly higher response rate coupled with sustained longer-term
benefits, positioning them as a potentially valuable component of a more effective mental health
treatment model.
Page 16 of 22
REFERENCES
Abraham, Henry David, Una D Mccann, and George A Ricaurte. "Psychedelic drugs."
Neuropsychopharmacology: the fifth generation of progress. (2002): 1545-56.
Abuzzahab, F. S., Sr., and B. J. Anderson. "A review of LSD treatment in alcoholism." [In eng].
Int Pharmacopsychiatry 6, no. 4 (1971): 223-35.
Aday, J. S., C. M. Mitzkovitz, E. K. Bloesch, C. C. Davoli, and A. K. Davis. "Long-term effects
of psychedelic drugs: A systematic review." [In eng]. Neurosci Biobehav Rev 113 (Jun
2020): 179-89.
Akers, Brian P., Juan Francisco Ruiz, Alan Piper, and Carl A. P. Ruck. "A Prehistoric Mural in
Spain Depicting Neurotropic Psilocybe Mushrooms?". Economic Botany 65, no. 2
(2011/06/01 2011): 121-28.
Andersen, K. A. A., R. Carhart-Harris, D. J. Nutt, and D. Erritzoe. "Therapeutic effects of classic
serotonergic psychedelics: A systematic review of modern-era clinical studies." [In eng].
Acta Psychiatr Scand (Oct 30 2020).
Barron, Frank, Murray E. Jarvik, and Sterling Bunnell. "The Hallucinogenic Drugs." Scientific
American 210, no. 4 (1964): 29-37.
Belouin, S. J., and J. E. Henningfield. "Psychedelics: Where we are now, why we got here, what
we must do." [In eng]. Neuropharmacology 142 (Nov 2018): 7-19.
Berman, R. M., A. Cappiello, A. Anand, D. A. Oren, G. R. Heninger, D. S. Charney, and J. H.
Krystal. "Antidepressant effects of ketamine in depressed patients." [In eng]. Biol
Psychiatry 47, no. 4 (Feb 15 2000): 351-4.
Bewley-Taylor, David R. "Challenging the UN drug control conventions: problems and
possibilities." International Journal of Drug Policy 14, no. 2 (2003/04/01/ 2003): 171-79.
Boakes, R. J., P. B. Bradley, I. Briggs, and A. Dray. "Antagonism of 5-hydroxytryptamine by LSD
25 in the central nervous system: a possible neuronal basis for the actions of LSD 25." [In
eng]. British journal of pharmacology 40, no. 2 (1970): 202-18.
Bowers, M. B., Jr., and D. X. Freedman. ""Psychedelic" experiences in acute psychoses." [In eng].
Arch Gen Psychiatry 15, no. 3 (Sep 1966): 240-8.
Breeksema, J. J., A. R. Niemeijer, E. Krediet, E. Vermetten, and R. A. Schoevers. "Psychedelic
Treatments for Psychiatric Disorders: A Systematic Review and Thematic Synthesis of
Patient Experiences in Qualitative Studies." [In eng]. CNS Drugs 34, no. 9 (Sep 2020):
925-46.
Byock, I. "Taking Psychedelics Seriously." [In eng]. J Palliat Med 21, no. 4 (Apr 2018): 417-21.
Canal, C. E. "Serotonergic Psychedelics: Experimental Approaches for Assessing Mechanisms of
Action." [In eng]. Handb Exp Pharmacol 252 (2018): 227-60.
Carbonaro, T. M., M. P. Bradstreet, F. S. Barrett, K. A. MacLean, R. Jesse, M. W. Johnson, and
R. R. Griffiths. "Survey study of challenging experiences after ingesting psilocybin
mushrooms: Acute and enduring positive and negative consequences." [In eng]. J
Psychopharmacol 30, no. 12 (Dec 2016): 1268-78.
Page 17 of 22
Carhart-Harris, R. L. "How do psychedelics work?" [In eng]. Curr Opin Psychiatry 32, no. 1 (Jan
2019): 16-21.
Carhart-Harris, R. L., D. Erritzoe, E. Haijen, M. Kaelen, and R. Watts. "Psychedelics and
connectedness." [In eng]. Psychopharmacology (Berl) 235, no. 2 (Feb 2018): 547-50.
———. "Psychedelics and connectedness." Psychopharmacology 235, no. 2 (2018/02/01 2018):
547-50.
Carhart-Harris, R. L., and G. M. Goodwin. "The Therapeutic Potential of Psychedelic Drugs: Past,
Present, and Future." [In eng]. Neuropsychopharmacology 42, no. 11 (Oct 2017): 2105-13.
Carhart-Harris, R. L., and D. J. Nutt. "Serotonin and brain function: a tale of two receptors." [In
eng]. J Psychopharmacol 31, no. 9 (Sep 2017): 1091-120.
Carhart-Harris, Robin L., Suresh Muthukumaraswamy, Leor Roseman, Mendel Kaelen, Wouter
Droog, Kevin Murphy, Enzo Tagliazucchi, et al. "Neural correlates of the LSD experience
revealed by multimodal neuroimaging." [In eng]. Proceedings of the National Academy of
Sciences of the United States of America 113, no. 17 (2016): 4853-58.
Carod-Artal, F. J. "Hallucinogenic drugs in pre-Columbian Mesoamerican cultures." [In eng
spa]. Neurologia 30, no. 1 (Jan-Feb 2015): 42-9.
Casselman, I., C. J. Nock, H. Wohlmuth, R. P. Weatherby, and M. Heinrich. "From local to global-
fifty years of research on Salvia divinorum." [In eng]. J Ethnopharmacol 151, no. 2 (Feb 3
2014): 768-83.
Cassels, B. K., and P. Sáez-Briones. "Dark Classics in Chemical Neuroscience: Mescaline." [In
eng]. ACS Chem Neurosci 9, no. 10 (Oct 17 2018): 2448-58.
Castellanos, J. P., C. Woolley, K. A. Bruno, F. Zeidan, A. Halberstadt, and T. Furnish. "Chronic
pain and psychedelics: a review and proposed mechanism of action." [In eng]. Reg Anesth
Pain Med 45, no. 7 (Jul 2020): 486-94.
Chi, T., and J. A. Gold. "A review of emerging therapeutic potential of psychedelic drugs in the
treatment of psychiatric illnesses." [In eng]. J Neurol Sci 411 (Apr 15 2020): 116715.
Chi, Tingying, and Jessica A. Gold. "A review of emerging therapeutic potential of psychedelic
drugs in the treatment of psychiatric illnesses." Journal of the Neurological Sciences 411
(2020/04/15/ 2020): 116715.
Cuijpers, P., A. Stringaris, and M. Wolpert. "Treatment outcomes for depression: challenges and
opportunities." [In eng]. Lancet Psychiatry 7, no. 11 (Nov 2020): 925-27.
Dalgarno, P. "Subjective effects of Salvia divinorum." [In eng]. J Psychoactive Drugs 39, no. 2
(Jun 2007): 143-9.
Delgado, P. L., and F. A. Moreno. "Hallucinogens, serotonin and obsessive-compulsive disorder."
[In eng]. J Psychoactive Drugs 30, no. 4 (Oct-Dec 1998): 359-66.
Denson, R., and D. Sydiaha. "A controlled study of LSD treatment in alcoholism and neurosis."
[In eng]. Br J Psychiatry 116, no. 533 (Apr 1970): 443-5.
Dos Santos, R. G., J. C. Bouso, MÁ Alcázar-Córcoles, and J. E. C. Hallak. "Efficacy, tolerability,
and safety of serotonergic psychedelics for the management of mood, anxiety, and
Page 18 of 22
substance-use disorders: a systematic review of systematic reviews." [In eng]. Expert Rev
Clin Pharmacol 11, no. 9 (Sep 2018): 889-902.
Dyck, E. "Flashback: psychiatric experimentation with LSD in historical perspective." [In eng].
Can J Psychiatry 50, no. 7 (Jun 2005): 381-8.
Ebeid, F. S. E. "COVID-19 effect on clinical research: Single-site risk management experience."
[In eng]. Perspect Clin Res 11, no. 3 (Jul-Sep 2020): 106-10.
Eisner, B. "Set, setting, and matrix." [In eng]. J Psychoactive Drugs 29, no. 2 (Apr-Jun 1997):
213-6.
Faillace, L. A., A. Vourlekis, and S. Szara. "Hallucinogenic drugs in the treatment of alcoholism:
a two-year follow-up." [In eng]. Compr Psychiatry 11, no. 1 (Jan 1970): 51-6.
Freedman, D. X. "Effects of LSD-25 on brain serotonin." [In eng]. J Pharmacol Exp Ther 134
(Nov 1961): 160-6.
———. "Hallucinogenic drug research--if so, so what? Symposium summary and commentary."
[In eng]. Pharmacol Biochem Behav 24, no. 2 (Feb 1986): 407-15.
———. "The psychopharmacology of hallucinogenic agents." [In eng]. Annu Rev Med 20 (1969):
409-18.
Fuentes, J. J., F. Fonseca, M. Elices, M. Farré, and M. Torrens. "Therapeutic Use of LSD in
Psychiatry: A Systematic Review of Randomized-Controlled Clinical Trials." [In eng].
Front Psychiatry 10 (2019): 943.
Gabay, Michael. "The federal controlled substances act: schedules and pharmacy registration." [In
eng]. Hospital pharmacy 48, no. 6 (2013): 473-74.
Galvão-Coelho, N. L., W. Marx, M. Gonzalez, J. Sinclair, M. de Manincor, D. Perkins, and J.
Sarris. "Classic serotonergic psychedelics for mood and depressive symptoms: a meta-
analysis of mood disorder patients and healthy participants." [In eng].
Psychopharmacology (Berl) 238, no. 2 (Feb 2021): 341-54.
Geiger, H. A., M. G. Wurst, and R. N. Daniels. "DARK Classics in Chemical Neuroscience:
Psilocybin." [In eng]. ACS Chem Neurosci 9, no. 10 (Oct 17 2018): 2438-47.
Giarman, N. J., and D. X. Freedman. "Biochemical Aspects of the Actions of Psychotomemetic
Drugs." [In eng]. Pharmacol Rev 17 (Mar 1965): 1-25.
Griffiths, R. R., M. W. Johnson, M. A. Carducci, A. Umbricht, W. A. Richards, B. D. Richards,
M. P. Cosimano, and M. A. Klinedinst. "Psilocybin produces substantial and sustained
decreases in depression and anxiety in patients with life-threatening cancer: A randomized
double-blind trial." [In eng]. J Psychopharmacol 30, no. 12 (Dec 2016): 1181-97.
Griffiths, R. R., M. W. Johnson, W. A. Richards, B. D. Richards, U. McCann, and R. Jesse.
"Psilocybin occasioned mystical-type experiences: immediate and persisting dose-related
effects." [In eng]. Psychopharmacology (Berl) 218, no. 4 (Dec 2011): 649-65.
Griffiths, R. R., W. A. Richards, U. McCann, and R. Jesse. "Psilocybin can occasion mystical-type
experiences having substantial and sustained personal meaning and spiritual significance."
[In eng]. Psychopharmacology (Berl) 187, no. 3 (Aug 2006): 268-83; discussion 84-92.
Page 19 of 22
Grinspoon, L., and J. B. Bakalar. "Can drugs be used to enhance the psychotherapeutic process?"
[In eng]. Am J Psychother 40, no. 3 (Jul 1986): 393-404.
———. Psychedelic Drugs Reconsidered. New York, NY: Basic Books, 1979.
Grof, S. "Foreword in LSD: My Problem Child, by Albert Hofmann." In LSD: My Problem Child.
Santa Cruz, CA: Multidisciplinary Association for Psychedelic Studies (MAPS), 2005.
Grof, S., L. E. Goodman, W. A. Richards, and A. A. Kurland. "LSD-Assisted Psychotherapy in
Patients with Terminal Cancer." International Pharmacopsychiatry 8 (1973): 129-44.
Hartogsohn, I. American Trip: Set, Setting, and Psychedelic Experience in the Twenteith Century.
Cambridge, Massachusetts: The MIT Press, 2020.
———. American Trip: Set, Setting, and Psychedelic Experience in the Twentieth Century.
Cambridge, Massachusetts: The MIT Press, 2020.
Hofmann, A. LSD: My Problem Child. Santa Cruz, CA: Multidisciplinary Association for
Psychedelic Studies (MAPS), 2009.
———. "Psychotomimetic drugs; chemical and pharmacological aspects." [In eng]. Acta Physiol
Pharmacol Neerl 8 (Jun 1959): 240-58.
Holoyda, Brian. "The Psychedelic Renaissance and Its Forensic Implications." Journal of the
American Academy of Psychiatry and the Law Online (2020): JAAPL.003917-20.
Johnson, M. W., A. Garcia-Romeu, M. P. Cosimano, and R. R. Griffiths. "Pilot study of the 5-
HT2AR agonist psilocybin in the treatment of tobacco addiction." [In eng]. J
Psychopharmacol 28, no. 11 (Nov 2014): 983-92.
Johnson, M. W., P. S. Hendricks, F. S. Barrett, and R. R. Griffiths. "Classic psychedelics: An
integrative review of epidemiology, therapeutics, mystical experience, and brain network
function." [In eng]. Pharmacol Ther 197 (May 2019): 83-102.
Krebs, T. S., and PØ Johansen. "Lysergic acid diethylamide (LSD) for alcoholism: meta-analysis
of randomized controlled trials." [In eng]. J Psychopharmacol 26, no. 7 (Jul 2012): 994-
1002.
Kyzar, E. J., C. D. Nichols, R. R. Gainetdinov, D. E. Nichols, and A. V. Kalueff. "Psychedelic
Drugs in Biomedicine." [In eng]. Trends Pharmacol Sci 38, no. 11 (Nov 2017): 992-1005.
Leary, T., R. Metzner, and R. Alpert. The Psychedelic Experience. New York, NY: Citadel Press
Books, 1964.
Liechti, M. E. "Modern Clinical Research on LSD." [In eng]. Neuropsychopharmacology 42, no.
11 (Oct 2017): 2114-27.
Listos, J., A. Merska, and S. Fidecka. "Pharmacological activity of salvinorin A, the major
component of Salvia divinorum." [In eng]. Pharmacol Rep 63, no. 6 (2011): 1305-9.
Ludwig, A., J. Levine, L. Stark, and R. Lazar. "A clinical study of LSD treatment in alcoholism."
[In eng]. Am J Psychiatry 126, no. 1 (Jul 1969): 59-69.
Lugo-Radillo A Md, PhD, and Jl Md Cortes-Lopez. "Long-term Amelioration of OCD Symptoms
in a Patient with Chronic Consumption of Psilocybin-containing Mushrooms." [In eng]. J
Psychoactive Drugs (Nov 22 2020): 1-3.
Page 20 of 22
Luoma, J. B., C. Chwyl, G. J. Bathje, A. K. Davis, and R. Lancelotta. "A Meta-Analysis of
Placebo-Controlled Trials of Psychedelic-Assisted Therapy." [In eng]. J Psychoactive
Drugs (Jun 12 2020): 1-11.
Madsen, M. K., P. M. Fisher, D. S. Stenbæk, S. Kristiansen, D. Burmester, S. Lehel, T. Páleníček,
et al. "A single psilocybin dose is associated with long-term increased mindfulness,
preceded by a proportional change in neocortical 5-HT2A receptor binding." [In eng]. Eur
Neuropsychopharmacol 33 (Apr 2020): 71-80.
Mertens, L. J., M. B. Wall, L. Roseman, L. Demetriou, D. J. Nutt, and R. L. Carhart-Harris.
"Therapeutic mechanisms of psilocybin: Changes in amygdala and prefrontal functional
connectivity during emotional processing after psilocybin for treatment-resistant
depression." [In eng]. J Psychopharmacol 34, no. 2 (Feb 2020): 167-80.
Mithoefer, M. C., M. T. Wagner, A. T. Mithoefer, L. Jerome, and R. Doblin. "The safety and
efficacy of {+/-}3,4-methylenedioxymethamphetamine-assisted psychotherapy in subjects
with chronic, treatment-resistant posttraumatic stress disorder: the first randomized
controlled pilot study." [In eng]. J Psychopharmacol 25, no. 4 (Apr 2011): 439-52.
Mithoefer, Michael C., Ann T. Mithoefer, Allison A. Feduccia, Lisa Jerome, Mark Wagner, Joy
Wymer, Julie Holland, et al. "3,4-methylenedioxymethamphetamine (MDMA)-assisted
psychotherapy for post-traumatic stress disorder in military veterans, firefighters, and
police officers: a randomised, double-blind, dose-response, phase 2 clinical trial." The
Lancet Psychiatry 5, no. 6 (2018/06/01/ 2018): 486-97.
Muschamp, J. W., M. J. Regina, E. M. Hull, J. C. Winter, and R. A. Rabin. "Lysergic acid
diethylamide and [-]-2,5-dimethoxy-4-methylamphetamine increase extracellular
glutamate in rat prefrontal cortex." [In eng]. Brain Res 1023, no. 1 (Oct 8 2004): 134-40.
Muttoni, S., M. Ardissino, and C. John. "Classical psychedelics for the treatment of depression
and anxiety: A systematic review." [In eng]. J Affect Disord 258 (Nov 1 2019): 11-24.
Naftulin, J. "Gwyneth Paltrow sent her employees to take psychedelic mushrooms in Jamaica. One
staffer said she felt like she'd undergone 5 years of therapy.". New York, NY, 2020.
Nichols, D. E. "Chemistry and Structure-Activity Relationships of Psychedelics." [In eng]. Curr
Top Behav Neurosci 36 (2018): 1-43.
———. "Dark Classics in Chemical Neuroscience: Lysergic Acid Diethylamide (LSD)." [In eng].
ACS Chem Neurosci 9, no. 10 (Oct 17 2018): 2331-43.
———. "Psychedelics." [In eng]. Pharmacol Rev 68, no. 2 (Apr 2016): 264-355.
Nichols, D. E., M. W. Johnson, and C. D. Nichols. "Psychedelics as Medicines: An Emerging New
Paradigm." [In eng]. Clin Pharmacol Ther 101, no. 2 (Feb 2017): 209-19.
Nichols, D. E., and A. T. Shulgin. "Sulfur analogs of psychotomimetic amines." [In eng]. J Pharm
Sci 65, no. 10 (Oct 1976): 1554-6.
Nour, M. M., and R. L. Carhart-Harris. "Psychedelics and the science of self-experience." [In eng].
Br J Psychiatry 210, no. 3 (Mar 2017): 177-79.
Nutt, David, and Robin Carhart-Harris. "The Current Status of Psychedelics in Psychiatry." JAMA
Psychiatry (2020).
Page 21 of 22
Pahnke, W. N., A. A. Kurland, L. E. Goodman, and W. A. Richards. "LSD-assisted psychotherapy
with terminal cancer patients." [In eng]. Curr Psychiatr Ther 9 (1969): 144-52.
Pollan, M. How to Change Your Mind. New York, NY: Penguin Press, 2018.
Reiche, S., L. Hermle, S. Gutwinski, H. Jungaberle, P. Gasser, and T. Majić. "Serotonergic
hallucinogens in the treatment of anxiety and depression in patients suffering from a life-
threatening disease: A systematic review." [In eng]. Prog Neuropsychopharmacol Biol
Psychiatry 81 (Feb 2 2018): 1-10.
Reiff, Collin M., Elon E. Richman, Charles B. Nemeroff, Linda L. Carpenter, Alik S. Widge,
Carolyn I. Rodriguez, Ned H. Kalin, and William M. McDonald. "Psychedelics and
Psychedelic-Assisted Psychotherapy." American Journal of Psychiatry 177, no. 5
(2020/05/01 2020): 391-410.
Riedlinger, T. J., and J. E. Riedlinger. "Psychedelic and entactogenic drugs in the treatment of
depression." [In eng]. J Psychoactive Drugs 26, no. 1 (Jan-Mar 1994): 41-55.
Rinkel, M. "Psychedelic drugs." [In eng]. Am J Psychiatry 122, no. 12 (Jun 1966): 1415-6.
Romeo, B., L. Karila, C. Martelli, and A. Benyamina. "Efficacy of psychedelic treatments on
depressive symptoms: A meta-analysis." [In eng]. J Psychopharmacol (May 25 2020):
269881120919957.
Rucker, J. J., L. A. Jelen, S. Flynn, K. D. Frowde, and A. H. Young. "Psychedelics in the treatment
of unipolar mood disorders: a systematic review." [In eng]. J Psychopharmacol 30, no. 12
(Dec 2016): 1220-29.
Schultes, R.E., A. Hofmann, and C. Ratsch. Plants of the Gods: Their Sacred, Healing, and
Hallucinogenic Powers. Rochester, VT: Healing Arts Press, 1998.
Shapiro, K. "Netflix And Trip: Take A Psychedelic Adventure In This Star-Studded
Documentary." New York, NY, 2020.
Sharp, Rachel. "The Hamilton Rating Scale for Depression." Occupational Medicine 65, no. 4
(2015): 340-40.
Shaw, E., and D. W. Woolley. "Some serotoninlike activities of lysergic acid diethylamide." [In
eng]. Science 124, no. 3212 (Jul 20 1956): 121-2.
Shore, P. A., S. L. Silver, and B. B. Brodie. "Interaction of serotonin and lysergic acid diethylamide
(LSD) in the central nervous system." [In eng]. Experientia 11, no. 7 (Jul 15 1955): 272-3.
Shulgin, A. T. "Chemistry of phenethylamines related to mescaline." [In eng]. J Psychedelic Drugs
11, no. 1-2 (Jan-Jun 1979): 41-52.
———. "Mescaline: the chemistry and pharmacology of its analogs." [In eng]. Lloydia 36, no. 1
(Mar 1973): 46-58.
———. "Profiles of psychedelic drugs." [In eng]. J Psychedelic Drugs 12, no. 2 (Apr-Jun 1980):
173-4.
———. "Psychotomimetic agents related to mescaline." [In eng]. Experientia 19 (Mar 15 1963):
127-8.
Page 22 of 22
Smart, R. G., T. Storm, E. F. Baker, and L. Solursh. "A controlled study of lysergide in the
treatment of alcoholism. 1. The effects on drinking behavior." [In eng]. Q J Stud Alcohol
27, no. 3 (Sep 1966): 469-82.
Smart, Reginald G., Thomas Storm, Earle F. W. Baker, and Lionel Solursh. "A Controlled Study
of Lysergide in the Treatment of Alcoholism. I. The Effects on Drinking Behavior."
Quarterly Journal of Studies on Alcohol 27, no. 3 (1966): 469-82.
Smith, C. M. "A new adjunct to the treatment of alcoholism: the hallucinogenic drugs." [In eng].
Q J Stud Alcohol 19, no. 3 (Sep 1958): 406-17.
Tenny, S., G. D. Brannan, J. Brannan, and N. C. Sharts-Hopko. "Qualitative Study." In StatPearls.
Treasure Island (FL): StatPearls Publishing LLC, 2020.
Trope, A., B. T. Anderson, A. R. Hooker, G. Glick, C. Stauffer, and J. D. Woolley. "Psychedelic-
Assisted Group Therapy: A Systematic Review." [In eng]. J Psychoactive Drugs 51, no. 2
(Apr-Jun 2019): 174-88.
Varker, T., L. Watson, K. Gibson, D. Forbes, and M.L. O’Donnell. "Efficacy of Psychoactive
Drugs for the Treatment of Posttraumatic Stress Disorder: A Systematic Review of
MDMA, Ketamine, LSD and Psilocybin." Journal of Psychoactive Drugs (2020): 1-11.
Vollenweider, F. X. "Advances and pathophysiological models of hallucinogenic drug actions in
humans: a preamble to schizophrenia research." [In eng]. Pharmacopsychiatry 31 Suppl 2
(Jul 1998): 92-103.
Vollenweider, F. X., and M. Kometer. "The neurobiology of psychedelic drugs: implications for
the treatment of mood disorders." [In eng]. Nat Rev Neurosci 11, no. 9 (Sep 2010): 642-
51.
Vollenweider, F. X., M. F. Vollenweider-Scherpenhuyzen, A. Bäbler, H. Vogel, and D. Hell.
"Psilocybin induces schizophrenia-like psychosis in humans via a serotonin-2 agonist
action." [In eng]. Neuroreport 9, no. 17 (Dec 1 1998): 3897-902.
Walsh, Charlotte. "Drugs, the Internet and Change." Journal of Psychoactive Drugs 43, no. 1
(2011/03/28 2011): 55-63.
Watts, Rosalind, Camilla Day, Jacob Krzanowski, David Nutt, and Robin Carhart-Harris.
"Patients’ Accounts of Increased “Connectedness” and “Acceptance” After Psilocybin for
Treatment-Resistant Depression." Journal of Humanistic Psychology 57, no. 5 (2017):
520-64.
Watts, Rosalind, and Jason B. Luoma. "The use of the psychological flexibility model to support
psychedelic assisted therapy." Journal of Contextual Behavioral Science 15 (2020/01/01/
2020): 92-102.
Weech, A. A., Jr., and R. E. Bibb. "Toward a rational approach to psychedelics: the controversy
over popular use from a clinical viewpoint." [In eng]. Compr Psychiatry 11, no. 1 (Jan
1970): 57-68.
Wilcox, J. A. "Psilocybin and Obsessive Compulsive Disorder." [In eng]. J Psychoactive Drugs
46, no. 5 (Nov-Dec 2014): 393-5.