Accepted Manuscript

Classic Psychedelics: An integrative review of epidemiology,

mystical experience, brain network function, and therapeutics

Matthew W. Johnson, Peter S. Hendricks, Frederick S. Barrett,

Roland R. Griffiths

PII: S0163-7258(18)30215-8
DOI: https://doi.org/10.1016/j.pharmthera.2018.11.010
Reference: JPT 7304
To appear in: Pharmacology and Therapeutics

Please cite this article as: Matthew W. Johnson, Peter S. Hendricks, Frederick S. Barrett,
Roland R. Griffiths , Classic Psychedelics: An integrative review of epidemiology,
mystical experience, brain network function, and therapeutics. Jpt (2018), https://doi.org/
10.1016/j.pharmthera.2018.11.010

This is a PDF file of an unedited manuscript that has been accepted for publication. As
a service to our customers we are providing this early version of the manuscript. The
manuscript will undergo copyediting, typesetting, and review of the resulting proof before
it is published in its final form. Please note that during the production process errors may
be discovered which could affect the content, and all legal disclaimers that apply to the
journal pertain.
 ACCEPTED MANUSCRIPT

P&T 23167

Classic Psychedelics: An integrative review of epidemiology, mystical experience, brain network

function, and therapeutics

Matthew W. Johnson1,* [email protected], Peter S. Hendricks2, Frederick S. Barrett1, Roland R.

Griffiths1,3

T
IP
CR
1
Johns Hopkins University School of Medicine, Department of Psychiatry and Behavioral Sciences

US
2
University of Alabama, Birmingham, Department of Health Behavior, School of Public Health

3
Johns Hopkins University School of Medicine, Department of Neuroscience
AN
M

*
Corresponding author.
ED
PT
CE
AC
 ACCEPTED MANUSCRIPT

Abstract

The purpose of this paper is to provide an integrative review and offer novel insights regarding

human research with classic psychedelics (classic hallucinogens), which are 5HT2AR agonists such as

lysergic acid diethylamide (LSD), mescaline, and psilocybin. Classic psychedelics have been administered

as sacraments since ancient times. They were of prominent interest within psychiatry and neuroscience

T
in the 1950s to 1960s, and during this time contributed to the emergence of the field of molecular

IP
neuroscience. Promising results were reported for treatment of both end-of-life psychological distress

CR
and addiction, and classic psychedelics served as tools for studying the neurobiological bases of

US
psychological disorders. Moreover, classic psychedelics were shown to occasion mystical experiences,

which are subjective experiences reported throughout different cultures and religions involving a strong
AN
sense of unity, among other characteristics. However, the recreational use of classic psychedelics and

their association with the counterculture prompted an end to human research with classic psychedelics
M

in the early 1970s. We review recent therapeutic studies suggesting efficacy in treating psychological
ED

distress associated with life-threatening diseases, treating depression, and treating nicotine and alcohol

addictions. We also describe the construct of mystical experience, and provide a comprehensive review
PT

of modern studies investigating classic psychedelic-occasioned mystical experiences and their

CE

consequences. These studies have shown classic psychedelics to fairly reliably occasion mystical

experiences. Moreover, classic psychedelic-occasioned mystical experiences are associated with

AC

improved psychological outcomes in both healthy volunteer and patient populations. We also review

neuroimaging studies that suggest neurobiological mechanisms of psychedelics. These studies have also

broadened our understanding of the brain, the serotonin system, and the neurobiological basis of

consciousness. Finally, we provide the most comprehensive review of epidemiological studies of classic

psychedelics to date. Notable among these are a number of studies which have suggested the possibility

that nonmedical naturalistic (non-laboratory) use of classic psychedelics is associated with positive
 ACCEPTED MANUSCRIPT

mental health and prosocial outcomes, although it is clear that some individuals are harmed by classic

psychedelics in non-supervised settings. Overall, these various lines of research suggest that classic

psychedelics might hold strong potential as therapeutics, and as tools for experimentally investigating

mystical experiences and behavioral-brain function more generally.

Keywords: classic psychedelics, LSD, psilocybin, cancer, depression, addiction

T
IP
CR
US
AN
M
ED
PT
CE
AC
 ACCEPTED MANUSCRIPT

Abbreviations

25I-NBOMe 4-Iodo-2,5-dimethoxy-N-[(2-methoxyphenyl)methyl]-benzeneethanamine

2C-B 2,5-Dimethoxy-4-bromophenethylamine

T
5-HT2AR Serotonin 2A receptor

IP
5-MEO-AMT 5-Methoxy-α-methyltryptamine

CR
5-MEO-DPT 5-Methoxy-N,N-dipropyltryptamine

US
5-MEO-DMT 5-Methoxy-N,N-dimethyltryptamine
AN
ACC Anterior cingulate cortex
M

AIRFA American Indian Religious Freedom Act

ED

AMT α-Methyltryptamine

BC Before Christ
PT

BOLD Blood oxygenation level dependent

CE

DAWN Drug Abuse Warning Network

AC

DEA Drug Enforcement Administration

DMN Default mode network

DMT Dimethyltryptamine

DSM-IV Diagnostic and Statistical Manual of Mental Disorders, 4th edition

ED Emergency department
 ACCEPTED MANUSCRIPT

EEG Electroencephalography

EMCDDA European Monitoring Centre for Drugs and Drug Addiction

fMRI Functional magnetic resonance imaging

HD-SS high-dose with standard support for spiritual-practice

T
HD-HS high-dos with high support for spiritual-practice

IP
kg Kilogram

CR
LD-SS Low-dose with standard support for spiritual-practice

US
LPC lateral parietal cortex
AN
LSA Lysergic acid amide
M

LSD Lysergic acid diethylamide

ED

MDMA 3,4- Methylenedioxymethamphetamine

MEG Magnetoencephalography
PT

MEQ30 30-item Mystical Experience Questionnaire

CE

MEQ43 43-item Mystical Experience Questionnaire

AC

mg Milligram

MPFC Medial prefrontal cortex

MRS Magnetic resonance spectroscopy

MTF Monitoring the Future

NAC Native American Church

 ACCEPTED MANUSCRIPT

NMDA N-methyl-D-aspartate

NSDUH National Survey on Drug Use and Health

PCC Posterior cingulate cortex

PET Positron emission tomography

T
sgACC Subgenual anterior cingulate

IP
SPECT Single photon emission computed tomography

CR
TAAR1 Trace amine-associated receptor 1

US
UDV União do Vegetal
AN
USDHHS United States Department of Health and Human Services
M
ED
PT
CE
AC
 ACCEPTED MANUSCRIPT

1. Introduction

1.1 Classic psychedelics defined

Classic psychedelics (or classic hallucinogens) are psychoactive compounds that exert effects

through agonist (including partial agonist) activity at the serotonin 2A receptor (5-HT2AR). Substantial

evidence suggests that 5-HT2A R, which is a G-protein-coupled receptor, is the most important receptor

T
IP
underlying classic psychedelic effects (Nichols, 2016). For example, rat studies have shown for a variety

CR
of classic psychedelics that 5-HT2A antagonists block the ability of classic psychedelics to serve as

discriminative stimuli (Glennon et al., 1983; Glennon et al., 1984). Human studies have also shown that

US
5-HT2A antagonism blocks the subjective and other effects of the classic psychedelic psilocybin (Kometer

et al., 2012; Quednow et al., 2012; Kometer et al., 2013; Vollenweider et al., 1998). Consistent with
AN
these findings, 5-HT2A receptor knock out mice do not exhibit the head-twitch response, a characteristic
M

rodent response to classic psychedelics (Halberstadt et al., 2011).

ED

Despite the primary role of 5-HT2A R agonism, other receptor-level mechanisms also contribute

to classic psychedelic effects. For example, 5-HT2C receptors, and for certain classic psychedelics, 5-HT1A
PT

play a role in classic psychedelic effects (Nichol, 2016; Halberstadt and Geyer, 2011). The effects of

particular psychedelics also involve non-5-HT receptors, for example, at high doses LSD has
CE

dopaminergic and adrenergic effects (Kyzar et al., 2017; Nichols, 2016). Multiple classic psychedelics
AC

activate TAAR1 (Brunzow et al., 2001; De Gregorio et al., 2016), suggesting the possibility that this

receptor may contribute to classic psychedelic effects (Kyzar et al., 2017). However, the behavioral and

subjective consequences of classic psychedelic activation of TAAR1 need to be investigated, and multiple

drugs other than classic psychedelics (e.g., amphetamine) also activate TAAR1, suggesting TAAR1

activation may not underlie effects that are quintessential to classic psychedelics. Beyond receptor

activation, classic psychedelics, but not a nonpsychoactive agonist of the 5-HT2A R, have been shown to
 ACCEPTED MANUSCRIPT

upregulate immediate early genes that encode for transcription factors, which in turn regulate multiple

genes (Gonzalez-Maeso et al., 2003). Many of the immediate early genes upregulated by classic

psychedelics code for proteins with involvement at the synapse, likely with effects on synaptic structure

in addition to neurotransmission, providing potential mechanisms underlying persisting as well as acute

classic psychedelic effects (Kyzar et al., 2017).

T
Classic psychedelics fall within one of two general structural categories. One category includes

IP
variations on the structure of tryptamine. Examples include LSD, psilocybin, and dimethyltryptamine

CR
(DMT), a psychoactive compound present in the South American sacramental beverage ayahuasca. The

US
second category includes variations on the structure of phenethylamine. One example is mescaline, the

main psychoactive agent in the peyote (Lophophora williamsii), San Pedro (Echinopsis pachanoi) and
AN
Peruvian torch (Echinopsis peruvianus) cacti (Nichols, 2016). A variety of synthetic compounds not

known to occur in nature also fall in the phenethylamine category (e.g., 2C-B, 25I-NBOMe). Indigenous
M

cultures in the Western Hemisphere have used compounds from both structural classes in the
ED

sacramental use of ayahuasca, psilocybin-containing mushrooms, and mescaline-containing cacti. One

analog of phenethylamine is methylenedioxymethamphetamine (MDMA), which causes psychoactive

PT

effects with only partial overlap with classic psychedelics, and which works primarily via serotonin
CE

release rather than 5-HT2AR agonism (Nichols et al., 1982). Like MDMA, other drugs sometimes labelled

as psychedelic (e.g., NMDA antagonists, anticholinergics, cannabinoids, salvinorin A, ibogaine) which are
AC

not classic psychedelics, will not be reviewed here because of their substantially differing mechanisms

and effects. Although reviews with some overlap to the present manuscript have been published (e.g.,

Barrett and Griffiths, 2018; dos Santos et al., 2016; Johnson and Griffiths, 2017; Mahapatra and Gupta,

2017; Nichols et al., 2017; Patra, 2016), none of these provide detailed coverage of each domain of the

present review (epidemiology, mystical experience, brain network function, and therapeutics).

1.2 Classic psychedelic effects

 ACCEPTED MANUSCRIPT

Perhaps the best description of a classic psychedelic is found in Grinspoon and Bakalar (1979,

page 9) who define it as “A drug which, without causing physical addiction, craving, major physiological

disturbances, delirium, disorientation, or amnesia, more or less reliably produces thought, mood, and

perceptual changes otherwise rarely experienced except in dreams, contemplative and religious

exaltation, flashes of vivid involuntary memory, and acute psychosis.” Classic psychedelics often cause

T
extreme changes in subjective experience during acute drug action (Passie et al., 2002), encompassing

IP
complex changes in affective, cognitive, and perceptual domains (Griffiths et al., 2006; Griffiths et al.,

CR
2011; Preller and Vollenweider, 2016). One type of subjective experience referred to as mystical-type

experience can be occasioned by administration of relatively high doses of classic psychedelics in

US
optimal settings (Gasser et al., 2014; Griffiths et al., 2006; Griffiths et al., 2011; Pahnke, 1963; Pahnke,
AN
1969; Pahnke and Richards, 1966; Richards et al., 1977), and will be discussed in detail in a subsequent

section.
M

The term “hallucinogen,” which has been widely applied to classic psychedelics in scientific
ED

circles, is not ideal because these substances do not typically produce frank hallucinations, and this

term, which connotes only perceptual effects, is an insufficient description of the often radical effects
PT

these drugs have on human consciousness and one’s sense of self. Therefore, the term “hallucinogen”
CE

has fallen out of favor, with a re-emergence of the scientific use of the term “psychedelic” to refer to

these substances (Nichols, 2016). The term “psychedelic,” which means “mind-manifesting” was coined
AC

by the pioneering classic psychedelic researcher Humphrey Osmond in 1957 (Dyck, 2006). As

summarized later in this review, recent psychological and biological research indicates the accuracy of

this term by suggesting this class of drugs to cause a non-ordinary and more variable form of

consciousness that is less centered on one’s normal sense of self, and that involves enhanced

autobiographical recollection (Carhart-Harris et al., 2012a; Carhart-Harris et al., 2012b).

 ACCEPTED MANUSCRIPT

Classic psychedelic administration entails risks. These fall into three major categories. One that

is relevant to any individual taking a sufficiently high dose of a psychedelics is an anxious, dysphoric,

confusing, and, less commonly, delusional acute reaction, often referred to as a “bad trip” in colloquial

language. Although these can be safely managed with safeguards in place within clinical research, these

challenging experiences can potentially lead to accidents or other dangerous behavior in unsupervised

T
settings (Carbonaro et al., 2016). Another risk is the exacerbation of psychotic disorders or instigating a

IP
prolonged psychotic reaction. For cases in which initial psychotic reactions within the lifetime occur

CR
after taking a classic psychedelic, psychotic vulnerability is suspected, but it is not possible to determine

if that individual would have eventually had a psychotic reaction or not if he/she had not been exposed

US
to the drug (Grinspoon and Bakalar, 1979). Early survey research of investigators who had administered
AN
classic psychedelics to humans suggest that prolonged psychiatric reactions (>48 hours) to be limited to

such vulnerable individuals, with only 1 case occurring among 1200 non-patient participants, and that
M

single patient was an identical twin of a schizophrenic patient. The same report found prolonged
ED

psychiatric reactions occurred at a rate of 1.8 per 1000 individuals for psychiatric patients. It also

reported no suicide attempts for the 1200 non-patient participants, with suicide attempts and
PT

completed suicides occurring at respective rates of 1.2 and 0.4 per 1000 patients (Cohen, 1960).
CE

Drawing from multiple previous reports of studies conducted in the 1960s and 1970s, Abraham et al.

(1996) reported that rates of developing psychoses following the administration of LSD range from .08%
AC

to 4.6%, with higher rates among psychiatric patients. Screening of psychotic disorders and vulnerability

is therefore an important safeguard against such psychiatric reactions in the vulnerable (Johnson et al.,

2008). It should be noted that the acute anxious, dysphoric, confusing, and/or delusional reactions

discussed above have sometimes been studied as psychosis symptoms, and therefore classic

psychedelics have been sometimes been considered to model psychotic symptoms (e.g., Gouzoulis-

Mayfrank et al., 1998; Gouzoulis-Mayfrank et al., 2005; Heekeren et al., 2007; Hoch, 1951; Hoffer et al.,
 ACCEPTED MANUSCRIPT

1954; Vollenweider et al., 1998; Halberstadt and Geyer 2013; Murray et al., 2013). However, important

differences have been demonstrated. For example, in healthy participants, classic psychedelics effects

show some similarity to, or model, the positive (e.g., thought disorder, inappropriate affect) but not

negative symptoms (e.g., flat affect, lack of motivation) of psychotic disorders (Gouzoulis-Mayfrank et

al., 2005; Heekeren et al., 2007). Perhaps more importantly, these drug-occasioned adverse subjective

T
experiences differ from psychotic disorders in that they have a clear cause (i.e., acute drug effects), and

IP
they resolve at the resolution of drug effects in the overwhelming majority of psychiatrically screened

CR
populations under appropriate safeguards as discussed above (e.g. Cohen, 1960; Johnson et al., 2008).

However, such adverse subjective experiences in unscreened and unsupervised individuals appear to

US
precipitate enduring psychotic reactions among some individuals (e.g., 3 among 1993 individuals who
AN
endorsed adverse subjective experiences in a survey focused on such experiences; Carbonaro et al.,

2016).
M

Another aspect of risk is that classic psychedelics modestly raise blood pressure and heart rate
ED

during their acute course of effects (Griffiths et al., 2006; Griffith et al., 2011; Hassler et al., 2004; Isbell,

1959; Strassman and Qualls, 1994; Gouzoulis-Mayfrank, et al., 1999a; Passie et al., 2002; Wolbach, et al.,
PT

1962a; Wolbach et al., 1962b). Therefore, those with severe cardiac disease should be excluded
CE

(Johnson et al., 2008). Adverse events that can be caused by the administration of classic psychedelics,

but that do not pose substantial obstacles for their clinical administration to most individuals, are dose-
AC

related headaches (Johnson et al., 2012), relatively low ratings of nausea (Griffiths et al., 2011;

Carbonaro et al., 2018), and relatively infrequent vomiting (e.g., 2 of 20 participants vomited after

receiving a high dose of 30 mg/70 kg psilocybin, although no participants vomited after 10 or 20 mg/70

kg; Carbonaro et al., 2018). A review of the risks of human classic psychedelic administration research

and guidelines for minimizing these risks (Johnson et al., 2008), as well as a review of public health
 ACCEPTED MANUSCRIPT

harms associated with psilocybin and other classic psychedelics (Johnson et al., 2018), are available

elsewhere.

1.3 Pre-historical and historical use of classic psychedelics

Classic psychedelic use by humans appears to be ancient (e.g., Akers et al., 2011; Bruhn et al.,

2002; Carod-Artal and Vázquez-Cabrera 2006). Among the varied indigenous societies that have used

T
IP
them, classic psychedelics are widely considered sacraments for use in religious and/or healing contexts

CR
(Johnson et al., 2008; Schultes, 1969; Schultes et al., 2001). Although mescaline was isolated and

identified as the main psychoactive compound in peyote around the turn of the century (Heffter, 1898),

US
it was not until after nearly a half century later, when the psychoactive effects of the synthetic

compound LSD were discovered using astonishingly low sub-milligram human doses (Hofmann and Ott,
AN
1980), that clinical interest in classic psychedelics began in earnest (Grinspoon and Bakalar, 1979).
M

Classic psychedelics attracted great interest within psychiatry and the emergent fields of molecular

neuroscience and the neuroscience of serotonin within the 1950s to 1960s (Grinspoon, 1981). Promising
ED

results were reported for both end-of-life psychological distress and addiction, and classic psychedelics
PT

served as tools for studying the biological bases of psychological disorders. The most promising

indications examined for classic psychedelic treatment were cancer-related psychological distress
CE

(Cohen, 1965; Kast, 1967; Kast and Collins, 1964; Kurland, 1985; Kurland et al., 1969; Kurland et al.,

1973; Pahnke et al., 1969; Richards, 1979; Richards et al., 1972; Richards et al., 1980) and addiction
AC

(Bowen et al., 1970; Chwelos et al., 1959; Hollister et al., 1969; Kurland et al., 1971; Ludwig et al., 1969;

Savage and McCabe, 1973; Tomsovic and Edwards, 1970). Despite promising findings, this earlier era of

human research with classic psychedelics came to a stop in the early 1970s because use of the

compounds outside of controlled research settings had become popular and associated with the

counter-culture movement of the time (Stevens, 1988; Nutt, King, Nichols, 2013). After decades of
 ACCEPTED MANUSCRIPT

dormancy, classic psychedelic research re-emerged in the 1990s (e.g., Spitzer et al., 1996; Strassman et

al., 1994; Volenweider et al., 1997).

2. Epidemiology of classic psychedelic use

2.1 Historical background

T
Several lines of archaeological evidence suggest that humans have used classic psychedelics in

IP
sacramental healing contexts since prehistoric times (Guerra-Doce, 2015; Schultes, 1969). For instance,

CR
paintings and sculptures depict stylized humanoids with mushroom features (Froese et al., 2016),

peyote bulbs stored in southwestern Texas caves have been radiocarbon dated to 3780-3660 BC (El-

US
Seedi et al., 2005), and classic psychedelic alkaloids have been found in both artifacts and human
AN
skeletal remains (Guerra-Doce, 2014). It also has been speculated that the ritualistic sacrament soma,

mentioned in the ancient Indian Rig-Veda texts, contained psilocybin mushrooms, fly agaric, and/or
M

other psychoactive plants (Levitt, 2011; McKenna, 1993), and the ancient Greek drink kykeon, used as a
ED

ceremonial rite for millennia in Eleusis, may have contained ergoline alkaloids, including lysergic acid

amides (Webster, 2000). Nevertheless, the prevalence of classic psychedelic use prior to the 20th century
PT

is unknown.
CE

Scientists investigated the psychoactive effects of the peyote cactus in the late 19th and early

20th centuries, isolating its psychoactive component, mescaline (Bruhn and Holmstedt, 1979; Schultes,
AC

1969). In 1943 Albert Hofmann serendipitously discovered the psychedelic effects of LSD, which was

followed by widespread interest in the psychiatric applications of this novel compound (Hofmann, 1970;

Osmond, 1957). Shortly thereafter in 1955, banker and amateur mycologist R. Gordon Wasson traveled

to the Sierra Mazateca of southern Mexico to document the traditional indigenous use of psilocybin

mushrooms. The widely circulated American weekly news magazine Life published Wasson’s

experiences in 1957 (“Seeking the Magic Mushroom,” 1957), thrusting psilocybin mushrooms into the
 ACCEPTED MANUSCRIPT

public eye. Aided by several high profile advocates (e.g., Cary Grant, Ken Kesey, Timothy Leary, and Paul

McCartney; Lee and Shlain, 1992; Stevens, 1987) classic psychedelics were soon part of both the

Western cultural vernacular and the scientific and clinical pharmacopeia.

2.2 Early epidemiological surveys

Among the first epidemiological surveys on classic psychedelic use was Life Styles and Campus

T
IP
Communities: A Report of a Survey of American Colleges and Universities, funded by the National

CR
Institutes of Mental Health and conducted by Johns Hopkins University. First published in 1972 and later

included in the 1974 Recent Surveys of Nonmedical Drug Use: A Compendium of Abstracts, this study of

US
7,948 United States college students found that 8.6% reported having ever used a classic psychedelic in

1970 and 12.6% reported having ever used a classic psychedelic in 1971. Of the sample, 1.5% reported
AN
“regular use” of classic psychedelics, defined as using at least once every one to two weeks during the
M

academic year (Rossi et al., 1972; Glenn and Richards, 1974).

ED

Drug Experience, Attitudes, and Related Behavior among Adolescents and Adults: Detailed

Tabulation, conducted by the Response Analysis Corporation (Response Analysis Corporation, 1973),
PT

reported on a national cross-section of 2,411 United States adults surveyed in 1972. This report found

that 4.6% of all respondents reported having ever used LSD, with men (7.2%) reporting a higher
CE

prevalence than women (2.2%). Furthermore, 22% of 18 to 21 year-olds and 18.2% of 18 to 25 year-olds
AC

reported having ever used LSD. The Response Analysis Corporation also surveyed 880 United States

youth aged 12 to 17. Of these respondents, 4.8% reported having ever used LSD, with girls (5.4%)

reporting a slightly higher prevalence than boys (4.4%).

Two additional early surveys included a study of 5,050 United States college students (Gergen et

al., 1972; Glenn and Richards, 1974) and a study of 1,517 boys starting tenth grade in public high schools

in the fall of 1966 (Johnston, 1973). Of the United States college student respondents, 11.7% reported
 ACCEPTED MANUSCRIPT

having ever used LSD or mescaline. Moreover, of the tenth grade boys, 6.8% reported having ever used

classic psychedelics in some manner.

In sum, early epidemiological surveys were limited in scope (e.g., consisting of only youth or only

college students) and limited in size (880 to 7,948 volunteers), but suggest that classic psychedelic use

and LSD use in particular was not uncommon among adolescents and young adults in the late 1960s and

T
early 1970s.

IP
CR
2.3 The “Monitoring the Future” survey

Among the first systematic and rigorous epidemiological surveys to assess classic psychedelic

US
use was Monitoring the Future (MTF). Funded by the National Institute on Drug Abuse, MTF has

surveyed approximately 50,000 12th graders every year since 1975 and a similar number of 8th graders,
AN
10th graders, college students, and young adults every year since 1991 (Miech et al., 2016).
M

Figure 1 displays past 12 months prevalence of LSD use among 8th graders, 10th graders, 12th
ED

graders, college students, and young adults from 1975 to 2015 and Figure 2 presents past 12 months

prevalence of “hallucinogens other than LSD” use among these groups across the same time period.
PT

Although the aggregated non-LSD hallucinogens include, per MTF methods, the dissociative anesthetic
CE

phencyclidine, concentrated tetrahydrocannabinol, and unknown hallucinogens, it also includes the

classic psychedelics mescaline, peyote, and psilocybin. According to MTF, the majority of hallucinogens
AC

other than LSD use is accounted for by psilocybin. As seen in the Figure 1, past 12 months prevalence of

LSD use peaked in the mid-1990s for all groups before declining and remaining somewhat constant since

the early 2000s. As shown in Figure 2, past 12 months prevalence of hallucinogens other than LSD use

was at its highest point among 12th graders in the first year of the MTF survey in 1975, declined until

1992, then increased before reaching another high among all groups in the early 2000s. Past 12 months

prevalence of hallucinogens other than LSD use has steadily declined since this time. The prevalence of
 ACCEPTED MANUSCRIPT

lifetime use and past 30 days use, also estimated by MTF but not reported here, exhibit similar time

trends, though as expected the prevalence of lifetime use is greater and the prevalence of past 30 days

use is smaller than the prevalence of past 12 months use. It is noted that in Figure 2 the uniform spike in

prevalence among 8th, 10th, and 12th graders between 2000 and 2001 is likely due a change in methods in

which the term “shrooms” was added to the query assessing psilocybin use (Miech et al., 2016).

T
Figure 1

IP
CR
10.0%

9.0%

8.0%

US
7.0%

6.0%
AN
5.0%

4.0%

3.0%
M

2.0%

1.0%
ED

0.0%
1982

2001

2003
1975
1976
1977
1978
1979
1980
1981

1983
1984
1985
1986
1987
1988
1989
1990
1991
1992
1993
1994
1995
1996
1997
1998
1999
2000

2002

2004
2005
2006
2007
2008
2009
2010
2011
2012
2013
2014
2015
2016
PT

Year

8th Graders 10th Graders 12th Graders College Students Young Adults
CE
AC
 ACCEPTED MANUSCRIPT

Figure 2

10.0%
9.0%
8.0%
7.0%
6.0%
5.0%

T
4.0%

IP
3.0%
2.0%

CR
1.0%
0.0%
1991

2010
1975
1976
1977
1978
1979
1980
1981
1982
1983
1984
1985
1986
1987
1988
1989
1990

1992
1993
1994
1995
1996
1997
1998
1999
2000
2001
2002
2003
2004
2005
2006
2007
2008
2009

2011
2012
2013
2014
2015
2016
US
Year

8th Graders 10th Graders 12th Graders College Students Young Adults
AN
2.4 National Survey on Drug Use and Health
M

The National Survey on Drug Use and Health (NSDUH) of the Substance Abuse and Mental
ED

Health Services Administration of the United States Department of Health and Human Services
PT

(USDHHS) has been conducted since 1979 to estimate the prevalence of substance use and mental

illness in the general United States civilian non-institutionalized population (aged 12 and older; United
CE

States Department of Health and Human Services, n.d., 1991a, 1991b, 1994a, 1994b, 1995 -2000, 2006a,
AC

2006b, 2006c, 2012c, 2012d, 2012e, 2012f, 2012g, 2012h, 2013, 2014a, 2014b, 2014c, 2014d, 2014e,

2014f, 2015, 2016). Initially the NSDUH queried respondents as to how many times they had used a

“hallucinogen” (including the dissociative anesthetic phencyclidine) in their lifetime, making it difficult to

determine the prevalence of classic psychedelic use. In 1985, the NSDUH began to query respondents

with regard to specific substances used, allowing for estimates of the lifetime prevalence of LSD, peyote,

mescaline, and psilocybin use. These data are presented in Figure 3 below.
 ACCEPTED MANUSCRIPT

Figure 3

12.0%

10.0%

8.0%

T
IP
6.0%

CR
4.0%

US
2.0%

0.0%
AN
1995

2009
1985
1988
1990
1991
1992
1993
1994

1996
1997
1998
1999
2000
2001
2002
2003
2004
2005
2006
2007
2008

2010
2011
2012
2013
2014
2015
Lifetime LSD Use Lifetime Peyote Use Lifetime Mescaline Use Lifetime Psilocybin Use
M
ED

As seen in this figure, whereas the lifetime prevalence of peyote and mescaline use has

remained relatively constant since 1985, the lifetime prevalence of LSD and psilocybin use increased
PT

between 1985 and the early 2000s. Whereas the lifetime prevalence of LSD use has slightly decreased

since the early 2000s, the lifetime prevalence of psilocybin use has slightly increased since this time. It is
CE

noted that differences in time trends between the NSDUH and MTF are likely attributable to the
AC

younger demographic captured by MTF.

2.5 Drug Abuse Warning Network

Another important source of information with regard to prevalence of classic psychedelic use is

number of emergency department (ED) visits, or “cases,” related to these substances. The Drug Abuse

Warning Network (DAWN) was established in 1972 by the Drug Enforcement Administration (DEA) to

monitor drug-related ED cases. Data pertaining to ED cases associated with classic psychedelic use are
 ACCEPTED MANUSCRIPT

available from 2004 to 2011 (United States Department of Health and Human Services, 2012a, 2012b).

These data are presented in Figure 4 below. As shown in this figure, ED cases associated with classic

psychedelic use rose slightly from 2004 to 2011, increasing by approximately one case over this time.

“Miscellaneous hallucinogens” (defined as novel 2C-X compounds, Datura stramonium, mescaline,

morning glory seeds, psilocybin, Salvia divinorum, and “Hallucinogens Not Otherwise Specified”) account

T
for the highest percentage of ED cases among all psychedelic-associated categories, and some of these

IP
substances are not considered classic psychedelics (e.g., Salvia divinorum). The “Hallucinogens Not

CR
Otherwise Specified” category includes 5-MEO-AMT, 5-MEO-DPT, 5-MEO-DMT, AMT, ayahuasca, DMT,

LSA, nutmeg, and other purportedly hallucinogenic plants and seeds. Some of these substances also are

US
not considered classic psychedelics. Thus, classic psychedelics appear to account for a very small number
AN
of drug-related ED visits. Indeed, to place these findings in context, cocaine was associated an average

of 163.8 cases per 100,000 ED visits and opioids were associated with an average of 69.2 cases per
M

100,000 ED visits over the same seven year period. Of course, these reports may in part reflect the
ED

relative prevalence of psychedelic use as compared to cocaine and opioid use.

PT
CE
AC
 ACCEPTED MANUSCRIPT

Figure 4

2.5

T
Cases

1.5

IP
1

CR
0.5

US
0
2004 2005 2006 2007 2008 2009 2010 2011
AN
LSD Psilocybin Miscellaneous hallucinogens Hallucinogens NOS
M

2.6 DEA seizures

ED

The DEA provides drug seizure statistics by year on its website starting in 1986. The DEA reports

“hallucinogen” seizures in dosage units, which vary among these compounds. Furthermore, the
PT

“hallucinogen” category appears to encompass LSD and psilocybin mushrooms as well as the
CE

dissociative anesthetics phencyclidine and ketamine and the empathogen/entactogen MDMA. The DEA

drug seizure data are therefore weak indicators of the prevalence of classic psychedelic use, but are
AC

nonetheless presented here as they reflect trends in the illicit drug market. Figure 5 displays DEA

hallucinogen doses seized since 1985. As shown in this figure, there has been a decrease in seizures

since the early 2000s. In the year 2000, a large LSD manufacturing operation was uncovered by the DEA,

which likely explains the spike in seizures that year (DEA Website , 2016; DEA News Release , 2003). The

data for 2014 are cited as, “preliminary and subject to updating” although through 2018 they have not

changed.
 ACCEPTED MANUSCRIPT

Figure 5

35,000,000

30,000,000

25,000,000
Hallucinogen Doses

20,000,000

T
15,000,000

IP
10,000,000

CR
5,000,000

US
1996

2013
1986
1987
1988
1989
1990
1991
1992
1993
1994
1995

1997
1998
1999
2000
2001
2002
2003
2004
2005
2006
2007
2008
2009
2010
2011
2012

2014
Year
AN
2.7 Epidemiological surveys outside the United States
M

Although the most comprehensive epidemiological surveys have originated in the United States,
ED

a number of surveys outside of the United States inform the global prevalence of classic psychedelic use.

The European Monitoring Centre for Drugs and Drug Addiction (EMCDDA) has been pooling data
PT

intermittently from European Union countries since 1990. Among young adults aged 15 to 34, national
CE

surveys report past 12 months prevalence rates of less than 1% for LSD and psilocybin combined, though

respondents from Finland, the United Kingdom, the Netherlands, and the Czech Republic report slightly
AC

higher rates of use (1% to 2.3%; European Drug Report, 2016). England and Wales independently

monitor lifetime, past 12 months, and past 30 days prevalence of LSD use. Lifetime prevalence rates of

LSD use peaked in England and Wales in the late 1990s and early 2000s at approximately 6%. As of 2015,

lifetime prevalence of LSD use was 4.4%, past 12 months prevalence of LSD use was 0.2%, and past 30

days prevalence of LSD use approached 0% (EMCDDA, 2017).

 ACCEPTED MANUSCRIPT

The Global Drug Survey is an online self-selected survey of individuals sampled from the United

Kingdom (33.9%), Australia (35.9%), the United States (17.3%), the Eurozone (10%), and Canada (2.9%)

initiated in 2012 (Lawn et al., 2014). In total, the Global Drug Survey queried 22,289 individuals, 68.6% of

whom were male with an average age of 31.4 years. Figure 6 summarizes findings from the Global Drug

Survey. Of note, 6.2% of Global Drug Survey respondents reported microdosing, or using sub-perceptual

T
doses of classic psychedelics with the intent to improve mood, productivity, and creativity (Winstock et

IP
al., 2017). It is noted that because Global Drug Survey participants were self-selected, these statistics are

CR
not representative of the general population, and in all likelihood overestimate the prevalence of classic

psychedelic use.

Figure 6
US
AN
50.0%
45.0%
M

40.0%
35.0%
ED

30.0%
25.0%
PT

20.0%
Lifetime Use
15.0%
Past 12 Months Use
CE

10.0%
Past 30 Days Use
5.0%
0.0%
AC

Drug

The Australian Institute of Health and Welfare has collected data on illicit substance use since

1993. Survey methods are similar to the NSDUH, capturing use prevalence rates of variance substances
 ACCEPTED MANUSCRIPT

including “hallucinogens.” Though ketamine and MDMA are not included in the hallucinogen category,

those substances comprising hallucinogens are not specified. Nevertheless, in 1993 7.3% of respondents

(aged 14 and older) reported having ever used a hallucinogen. This figure rose to 9.9% in 1998 and

fluctuated around 7% in the early 2000s until peaking again in 2013 at 9.4%. Furthermore, in 1993 1.3%

of respondents reported using a hallucinogen in the past 12 months. This peaked in 1998 at 3.0% and

T
then steadily declined to 1.3% in 2013. With regard to frequency of use, 70.2% of respondents who

IP
endorsed having ever used a hallucinogen reported using hallucinogens once or twice per year

CR
(Australian Institute of Health and Welfare, 2014).

US
2.8 Special populations

The Native American Church (NAC), Sainto Daime Church, and União do Vegetal (UDV) use
AN
classic psychedelic compounds as part of their religious observances in the US and elsewhere. Prior to
M

the passage of the American Indian Religious Freedom Act (AIRFA) in 1994, which granted the NAC a

religious use exemption for peyote, between 1% and 2% of American Indians reported having ever used
ED

this substance. Following the passage of the AIRFA, approximately 10% of American Indians reported
PT

having ever used peyote. NAC membership is estimated at approximately 600,000 individuals (Prue,

2014). The Santo Daime Church reports that approximately 100,000 people participate in their
CE

ayahuasca ceremonies (santodaime.com/en/asks/#28), and the UDV claims over 17,000 members in

Brazil in addition to 270 members in the United States (udvusa.org). A number of studies indicate no
AC

harm associated with participation in these religious observances, and in fact several findings suggest a

protective effect with regard to mental health (e.g., Barbosa et al., 2009; Buoso et al., 2012; Doering-

Silva, 2005; Fabregas et al., 2010; Halpern et al., 2005, 2008; Miranda, 1995).

The United States military has a unique history with LSD, having tested the drug as a potential

incapacitating agent, without success, after its discovery by Albert Hofmann in 1943 (Lee and Shlain,
 ACCEPTED MANUSCRIPT

1992). Dr. James Ketchum, who was involved in testing LSD at the Army Chemical Center in the 1960s,

reported a reduced rate of later death (assessed between 1980 and 1981) among individuals who had

previously received LSD (between 1955 and 1975). Specifically, among over 100 individuals who

received LSD, only one death was recorded whereas 7.1 were expected to occur (Ketchum, 2006).

2.9 Population-level associations

T
IP
A number of recent studies have examined population-level associations of classic psychedelic

CR
use. Drawing data from multiple years of the NSDUH, Krebs and Johansen (2013) and Johansen and

Krebs (2015) found positive trends but no statistically significant associations between lifetime use of

US
classic psychedelics and mental health outcomes, and in fact found some evidence that lifetime use of

classic psychedelics was associated with a reduced likelihood of mental health problems. Drawing from a
AN
larger number of years of the NSDUH data than the Krebs and Johansen (2015) study but showing
M

similarly sized odds ratios, Hendricks et al. (2015a, 2015b) found that having ever used a classic

psychedelic and having ever used psilocybin in particular were both significantly associated with a
ED

decreased likelihood of psychological distress and suicidality. Argento et al. (2017) replicated and
PT

extended these findings by showing that having ever used a psychedelic, broadly defined (e.g., including

MDMA), predicted a decreased likelihood of suicidality among 766 female sex workers in British
CE

Columbia. Consistent with recent pilot trials on psilocybin-assisted treatment of addiction (Bogenschutz

et al., 2015; Johnson et al., 2014; Johnson et al. 2017a), Pisano et al. (2017) found that having ever used
AC

a classic psychedelic was associated with a decreased risk of opioid abuse and dependence across

multiple NSDUH years. Addressing a line of work that garnered research attention during the first wave

of classic psychedelic science (Arendsen-Hein, 1963; Leary, 1969; Tenenbaum, 1961), Hendricks et al.

(2014) found that naturalistic hallucinogen use predicted a reduced likelihood of supervision failure (i.e.,

criminal recidivism) among more than 25,000 individuals under community corrections supervision with

a history of substance involvement. Walsh et al. (2016) also found that naturalistic hallucinogen use
 ACCEPTED MANUSCRIPT

predicted reduced arrest for intimate partner violence among 302 jail inmates, and Hendricks et al.

(2018) found that having ever used a classic psychedelic was associated with a reduced likelihood of

larceny/theft and assault using multiple years of NSDUH data. It bears repeating, however, that

unsupervised classic psychedelic use can potentially result in dangerous behavior, and prompt or

exacerbate psychotic disorders among those predisposed to such disorders (Johnson et al., 2008).

T
Although no contemporary studies have reported psychoses following the administration of a classic

IP
psychedelic, rates for developing psychoses following the administration of LSD in studies conducted in

CR
the 1960s and 1970s range from .08% to 4.6%, with higher rates among psychiatric patients (Abraham et

al., 1996). Clearly then, despite these population-level associations, classic psychedelics are not without

US
risk, and use outside of approved clinical settings is strongly discouraged.
AN
3. Therapeutic effects
M

Here we review contemporary clinical research examining classic psychedelics in the treatment

of cancer-related psychological distress, and the treatment of addictions. One study examined the dose-
ED

related effects of psilocybin in the treatment of obsessive-compulsive disorder (Moreno et al., 2006).
PT

Although symptoms were reduced temporarily after psilocybin administration, the similar efficacy

observed for the high dose and very low dose administered in the study suggests the considerable
CE

possibility that results may have been driven by expectancy. Other case-series research has suggested

potential efficacy of classic psychedelics in the treatment of cluster headaches, which are notoriously
AC

painful and resistant to treatment (Sewell et al., 2006). These patient self-reports suggest that even very

low, sub-psychedelic doses of classic psychedelics may effectively abort and prevent cluster headaches.

However, because the potential mechanisms at play are likely distinct from the treatment of

psychological disorders reviewed herein, this research is not reviewed here. The laboratory clinical trials

and pilot studies discussed below have routinely reported the more common adverse events to be

expected among classic psychedelic administration studies, specifically, elevated blood pressure and
 ACCEPTED MANUSCRIPT

heart rate, psychological discomfort (e.g., anxious or dysphoric reactions), and physical distress (e.g.,

nausea, vomiting, and headache). While such adverse events are common, they can be managed with

appropriate safeguards (Johnson et al., 2008), and do not appear to preclude the possibility of

therapeutic benefit.

3.1 Cancer-related psychological distress

T
IP
All of studies reviewed in this section and the following Addiction section used a particular

CR
treatment approach which was first reported in the scientific literature in 1959 (Chwelos et al., 1959;

Majic et al., 2015), and which has come to be known as “psychedelic” psychotherapy. In contrast to the

US
“psycholytic” approach which used lower doses of classic psychedelics, the goal of the psychedelic

approach was to administer a high dose in order to occasion a mystical-type experience (sometimes
AN
referred to with related terms such as “peak experience” or “ego dissolution”) and subsequent behavior
M

change. In addition to the administration of a high dose of a classic psychedelic compound,

"psychedelic” psychotherapy includes preparation and rapport building with session facilitators before
ED

sessions occur, a comforting physical and interpersonal environment, the use of eyeshades to block
PT

visual stimuli and playing carefully selected music during sessions, and follow up discussion of the

session experience.
CE

Following up on the promising findings from trials conducted from the 1950s to 1970s using the
AC

classic psychedelics LSD and dipropyltryptamine (DPT) (Cohen, 1965; Kast, 1967; Kast and Collins, 1964;

Kurland, 1985; Kurland et al., 1969; Kurland et al., 1973; Pahnke et al., 1969; Richards, 1979; Richards et

al., 1972; Richards et al., 1980), a small pilot study in 2011 compared the effects of a moderate dose of

oral psilocybin (0.2 mg/kg) and niacin as a comparator compound within 12 participants with advanced-

stage cancer and clinically significant cancer-related anxiety meeting criteria for a DSM-IV anxiety-

related disorder (Grob et al., 2011). Importantly, there were no clinically significant adverse events
 ACCEPTED MANUSCRIPT

attributable to psilocybin. In a two-week follow-up after drug administration, psilocybin relative to

placebo showed a trend toward decreasing depression severity as measured by the Beck Depression

Inventory, and anxiety severity as measured by the State-Trait Anxiety Inventory. Relative to scores

assessed at study screening, mean depression scores were consistently reduced at each monthly follow

up session, up to the last follow up at 6-months, when this reduction was statistically significant.

T
Similarly, mean trait anxiety scores were consistently reduced compared to baseline at each month

IP
follow up, and this reduction was significant at the 3-month follow up. This study played an important

CR
role in suggesting that the effects reported for LSD in cancer patients in the earlier era of research are

likely relevant to psilocybin as well. Moreover, the study demonstrated safety of psilocybin in this

US
population.
AN
Two larger studies, both using a substantially higher dose of oral psilocybin, were recently

published (Griffiths et al., 2016; Ross et al., 2016). One study was conducted in 51 patients with a life-
M

threatening cancer diagnosis who met criteria for at least one DSM-IV mood- or anxiety-related disorder
ED

in relation to their cancer (Griffiths et al., 2016). Specifically, these disorders included chronic

adjustment disorder with anxiety, chronic adjustment disorder with mixed anxiety and depressed mood,
PT

dysthymic disorder, generalized anxiety disorder, and major depressive disorder. Each participant had
CE

two drug administration sessions: one in which a high oral dose of psilocybin (~0.31 or ~0.43 mg/kg) was

administered; and one in which a very low dose of psilocybin (~0.01 or ~0.04 mg/kg) was administered
AC

as a comparator condition, with the order of the two conditions counterbalanced across participants.

Volunteers and session monitors were informed that psilocybin would be administered in both sessions,

that the possible dose could range from negligible to high in both sessions, and that at least one session

would be at least a moderately-high dose. This instructional set, combined with the use of an inactive or

minimally active dose of psilocybin for the comparator condition, maximized expectancy effects for both

sessions, thereby increasing the likelihood of positive effects from the low dose and further eliminating
 ACCEPTED MANUSCRIPT

the expectancy that an active first session would necessarily be followed by a relatively inactive second

session. The high psilocybin dose, compared to the very low dose, significantly improved a variety

outcomes measures when measured 5 weeks after each session and before experiencing the other

session (if it was still forthcoming). Most astonishingly, results on a number of measures, including the

primary clinical outcome measures (Depression: Hamilton Depression Rating Scale, Beck Depression

T
Inventory; Anxiety: Hamilton Anxiety Rating Scale, State-Trait Anxiety Inventory) remained significantly

IP
and substantially reduced at the final 6-month follow up compared to screening scores, with

CR
approximately 60% of participants showing scores within the clinically normal range, constituting

remission. As discussed in more detail in a later section, ratings of mystical experience occasioned by

US
sessions mediated the effect of psilocybin condition on a number of clinical outcomes. No serious
AN
adverse effects attributable to psilocybin were observed.

The other study was conducted in 29 patients with a life-threatening cancer diagnosis who met
M

criteria for a DSM-IV anxiety-related disorder in relation to their cancer (Ross et al., 2016). Specifically,
ED

these disorders included adjustment disorder and generalized anxiety disorder. Each participant

participated in two drug administration sessions. A high oral dose of psilocybin (0.3 mg/kg) was
PT

administered in one session, and niacin was administered as a comparator compound in the other. The
CE

order of the two conditions was randomized for each participant. Consistent with the results of the

larger high-dose study (Griffiths et al., 2016), the high dose psilocybin condition caused significant
AC

improvements in a variety of outcome measures regardless of order of treatment conditions. At

approximately 6 months after treatment, anxiety and depression symptoms remained significantly and

substantially reduced compared to screening scores, with an approximately 60% remission rate for key

anxiety and depression outcome measures. Ratings of mystical experience were shown to be a mediator

of the relation between psilocybin administration and therapeutic effect of psilocybin on anxiety and

depression. A statistical mediator is a variable that underlies or explains the causal relationship between
 ACCEPTED MANUSCRIPT

two other variables. In this case, analysis suggested that the ability of psilocybin to cause positive

therapeutic change was due to psilocybin’s role in producing mystical-type experience (Baron and

Kenny, 1986). The different designs used by this study (Ross et al., 2016) and the previously described

high-dose psilocybin study (Griffiths et al., 2016) both resulted in surprisingly large and lasting

antidepressant and anxiolytic effects, providing complementary support for the efficacy of high-dose

T
psilocybin for cancer-related psychological distress. Like the previous studies, no serious adverse effects

IP
attributable to psilocybin were observed.

CR
Another recent study more directly replicated and extended the previous research examining

US
classic psychedelics in the treatment of cancer-related psychological distress, by examining the effects of

LSD (Gasser et al., 2014). Participants were individuals with anxiety associated with one of several life-
AN
threatening diseases. Six of these participants had cancer diagnoses, as did participants in the previously

described studies (Griffiths et al., 2016; Grob et al., 2011; Ross et al., 2016). Participants received 2 LSD
M

sessions that were separated by 2 to 3 weeks. Each qualifying participant was randomly assigned to
ED

receive either 200 (n=8) or 20 micrograms (n=3) of LSD in the context of psychedelic psychotherapy (as

in the psilocybin cancer studies), with the same dose delivered in each of the two sessions. The 20
PT

microgram dose was considered an active placebo because it was expected to result in mild, detectable
CE

effects but to not generally enhance therapeutic process. At a 2-month follow-up, significant reductions

in state anxiety as measured by the State-Trait Anxiety Inventory were observed for the experimental
AC

group receiving 200 micrograms of LSD in their sessions, and these approximate levels of improvement

were also observed at a 12-month follow up. In contrast, the active placebo group that received 20

micrograms of LSD in their sessions showed a trend for increased state anxiety at the 2 month follow up.

A similar reduction was observed for trait anxiety in the 200 microgram group, but this did not reach

statistical significance. The 20 microgram group showed a trend increased trait anxiety at the 2 month

follow up. After the 2 month follow up, participants in the 20 microgram active placebo group
 ACCEPTED MANUSCRIPT

underwent a “crossover” to receive the experimental dose of 200 micrograms in 2 sessions. This

resulted in trend decreases in state and trait anxiety 2 months later, and 12 month follow-up anxiety

scores similar to those in the experimental group. Like the studies described above examining psilocybin,

no serious adverse drug effects were reported.

3.2 Depression

T
IP
A small open-label pilot study of 12 patients recently examined psilocybin in treatment-resistant

CR
major depression (Carhart-Harris et al., 2016). This study involved two sessions separated by one week.

In the first session, patients were orally administered 10 mg of psilocybin. In the second session, 25 mg

US
of psilocybin was orally administered. A number of outcomes, including depression as measured by the

Quick Inventory of Depressive Symptoms, and anxiety as measured by the State-Trait Anxiety Inventory,
AN
showed statistically significant improvements as compared to screening measures, when assessed both
M

one week and three months after psilocybin treatment. No serious adverse events were attributable to

psilocybin administration. A follow up study reported results for an additional number of participants
ED

(for a total n=20) at 6 months post-treatment. Substantial reductions in depressive symptoms were
PT

significant at all time points observed post-treatment, including the 6-month follow up. Greater ratings

of mystical-type experience (measured by factors of unity, spiritual experience, and blissful state on the
CE

11-Dimension Altered States of Consciousness Questionnaire) and ratings of insight for the sessions

were significantly related to lower depression scores 5 weeks post-treatment (Carhart-Harris et al.,
AC

2018). From this same open-label study, an analysis of 16 patients undergoing fMRI found that increased

resting state connectivity within the default mode network (DMN) and between DMN (parahippocampal

cortex) and prefrontal cortices observed 1 day after the second of two psilocybin treatments was

predictive of clinical response 5 weeks post-treatment (Carhart-Harris et al., 2017). Also from the same

open-label study, an analysis of 19 participants undergoing fMRI showed increased amygdala response

to emotional faces 1 day after the second of two psilocybin treatments, a finding opposite in direction to
 ACCEPTED MANUSCRIPT

previous findings with SSRI treatment of depression (Roseman et al., 2017). These findings suggest

potential biological mechanisms for therapeutic efficacy in depression treatment which should be

confirmed in randomized treatment trials.

Consistent with the preliminary observations for psilocybin, several studies suggest ayahasca

may hold promise for the treatment of depression. One observational study of 57 non-patient

T
individuals attending ayahuasca ceremonies found significantly decreased ratings of depression and

IP
stress (and small, non-significant reductions in anxiety) on the 21 item Depression, Anxiety, and Stress

CR
Scale when assessed 1 day and 4 weeks after, compared to before, the ayahuasca ceremonies (Uthaug

US
et al., 2018 ). Ratings of depression and stress 1 day after the ceremonies were significantly related to

the extent of “ego dissolution” in regard to the ayahuasca experiences as rated on the Ego Dissolution
AN
Inventory. An open label study of ayahuasca administration (2.2 mL/kg body weight, with 0.8 mg/mL

DMT content), was conducted in 6 patients with recurrent major depressive disorder in an inpatient
M

psychiatric unit (Osório Fde et al., 2015). Ayahuasca administration was followed by statistically
ED

significant and substantial reductions in symptom ratings in the Hamilton Depression Rating Scale, the

Montgomery-Åsberg Depression Rating Scale, and the Brief Psychiatric Rating Scale anxious-depression
PT

subscale at 1, 7, and 21 days post-administration compared to baseline. Using similar methods, the
CE

same group replicated these findings in a larger sample of 17 patients with recurrent major depressive

disorder (Sanches et al., 2016). Using SPECT imaging, the study also found increased blood perfusion in
AC

areas involved in mood regulation (left nucleus accumbens, right insula, and left subgenual area) after

ayahuasca administration.

The only randomized trial of a classic psychedelic for treatment-resistant depression examined

ayahusaca (Palhano-Fontes et al., 2018). Patients (n=29 who received intervention) were randomized to

receive either ayahuasca (containing 0.36 mg/kg DMT; n=14) or placebo (n=15). Although the ayahuasca

group showed a trend for higher depressive symptom scores on the Montgomery-Åsberg Depression
 ACCEPTED MANUSCRIPT

Rating Scale and the Hamilton Depression Rating Scale before the intervention compared to the placebo

group, both scales showed significantly and substantially lower depressive symptoms in the ayahausca

group compared to the placebo group 7 days after treatment.

In response to promising results in the treatment of depression with classic psychedelics (both

within and outside of cancer contexts), a number of reviews and commentaries have been published. A

T
commonality is acknowledgement of promising findings but recognition of the early stages of this

IP
research and the need for larger studies investigating methodological variations, in particular the need

CR
for randomized research in non-cancer related treatment-resistant depression, continued research on

US
potential risks, and additional research on potential mechanisms (e.g., dos Santos et al., 2016;

Mahapatra and Gupta, 2017; Patra, 2016; Cowen, 2016; McCorvy et al., 2016). A challenge not typically
AN
recognized in commentaries is that, despite widespread agreement that systematic and rigorous

following is essential, substantial funding is required for large trials and mechanistic studies, and to date,
M

federal funding for such follow up research has not been provided. Hopefully, recent research on
ED

depression and other disorders has set the stage for a transition in which public funding for needed

follow up research may be forthcoming (Johnson, in press).

PT

3.3 Addiction
CE

Until recently, reviews of the older literature examining classic psychedelics in the treatment of
AC

addictions have concluded mixed results (Abuzzahab and Anderson, 1971; McGlothlin and Arnold, 1971;

Halpern, 1996; Mangini, 1998). However, a meta-analysis published in 2012 quantitatively analyzed the

effect sizes observed for all six of the studies that randomized alcohol dependent participants to LSD

treatment or comparator conditions and found robust support for the efficacy of LSD, showing, for

example, that LSD approximately doubled the odds of improved outcomes at the first follow-up (Krebs

and Johansen, 2012). In addition to this rigorous quantitative re-analysis of the previous era of research,
 ACCEPTED MANUSCRIPT

multiple recent clinical pilot studies have reinitiated interest in the use of classic psychedelics in the

treatment of addiction.

One small open-label pilot study of smoking cessation treatment administered psilocybin to 15

treatment-resistant, biologically confirmed smokers, along with cognitive behavioral therapy for tobacco

dependence (Johnson et al., 2014). On the target quit date, the timing of which was determined several

T
weeks beforehand, participants were orally administered ~0.29 mg/kg psilocybin. Two weeks later, a

IP
second oral dose of psilocybin (~0.43 mg/kg) was administered. Eight weeks after the target quite date,

CR
a third dose (~0.43 mg/kg) was administered. The study included the option to administer the ~0.29

US
mg/kg dose during the second and/or third psilocybin sessions dependent on participant response. The

treatment program included weekly cognitive behavioral therapy sessions that occurred until 10 weeks
AN
after the target quit date (except when a psilocybin session was scheduled). Results showed that 80% of

participants were biologically confirmed as abstinent at 6-months post-target quit date, and 60% of
M

participants biologically confirmed as abstinent at 2.5 years post-target quit date (Johnson et al., 2014;
ED

Johnson et al., 2017a). Although this pilot study contained no comparison group, the abstinence rates

were substantially higher than those typically observed in medication and/or behavioral smoking
PT

cessation therapies (e.g., typically ≤35% abstinence at 6 months; Johnson et al., 2014). Those
CE

participants who showed stronger mystical experiences on psilocybin session were more likely to be

successful in quitting smoking (Garcia-Romeu et al., 2014). Although spirituality is often an aspect of
AC

addiction recovery (e.g., Miller, 2004), we are aware of no data to indicate if psychedelic-occasioned

experiences are identical to those reported in addiction recovery (e.g., 12 step programs) using either

validated self-report instruments or at the neurobiological level. No serious adverse events were

attributed to psilocybin. A recent survey study examined individuals claiming to have quit or reduced

smoking due to a classic psychedelic experience and found that participants typically judged negative
 ACCEPTED MANUSCRIPT

affect withdrawal symptoms (e.g., depression, irritability, craving) to be much less severe compared to

previous occasions in which they quit smoking (Johnson et al., 2017b).

Another small open-label study tested psilocybin in the treatment of addiction, in this case,

alcohol dependence (Bogenschutz et al., 2015). Ten participants who met DSM-IV criteria for alcohol

dependence participated in up to two oral psilocybin sessions as part of a motivational enhancement

T
therapy program lasting 12 weeks. Upon at least 24 hours of alcohol abstinence, the first psilocybin

IP
session occurred, in which 0.3 mg/kg psilocybin was administered. A second dose of 0.4 mg/kg (or 0.3

CR
mg/kg depending on response in first session) was administered four weeks later for a subset of

US
volunteers. Percentage of drinking days and percentage of heavy drinking days significantly decreased

following the first psilocybin session. At 36 weeks after treatment, these self-reported drinking indices
AN
were still substantially lower than at screening. More specifically, mean percentage of drinking days

dropped from approximately 32.5% in the 4 weeks of treatment preceding the psilocybin session, to
M

approximately 12.5% in the 4 weeks following the psilocybin session, and approximately 17.5% at the
ED

final follow up period 21 to 32 weeks after the psilocybin session. Mean percentage of heavy drinking

days (i.e., ≥5 drinks for men, ≥4 drinks for women) dropped from approximately 26% in the 4 weeks of
PT

treatment preceding the psilocybin session, to approximately 8% in the 4 weeks following the psilocybin
CE

session, and approximately 13% at the final follow up period 21 to 32 weeks after the psilocybin session.

A significant relation was found between higher mystical-type experience scores in the first psilocybin
AC

session and decreased alcohol use. Importantly, there were no clinically significant adverse events

attributable to psilocybin.

4. Mystical experiences

Mystical-type or quantum change experiences are sometimes occasioned by classic psychedelics.

Mystical experiences refer to a class of experiences having a primary feature of a sense of the unity of all
 ACCEPTED MANUSCRIPT

people and things accompanied by a sense of reverence, and the authoritative truth value of the

experience (e.g., Stace, 1960a). Descriptions of spontaneously occurring mystical experiences date back

millennia to the early Indian Upanishads and the Greek philosopher Plotinus. Many reports of such

experiences have been catalogued and classified by theologians, psychologists, and philosophers (James,

1902; Stace, 1960a,b). Quantum change is a more recently introduced concept that has significant

T
overlap with mystical experience, but in addition to the phenomenology of the experience itself,

IP
quantum change emphasizes the persisting consequences caused by the experience. More specifically,

CR
quantum change experiences refer to sudden, distinctive, benevolent, and often profoundly meaningful

experiences that are said to result in personal transformations that affect a broad range of personal

US
emotions, cognitions and behaviors (Miller and C’de Baca, 2001; Miller, 2004). The phenomenon of
AN
quantum change is differentiated from the usual process of behavioral change, which occurs in small

incremental steps (James, 1902). Two subtypes of quantum change experiences have been proposed:
M

the mystical-type (which overlap with classic mystical experiences) and the insightful-type, which
ED

emphasize the importance of sudden and compelling personal insight into life problems or

circumstances. These overlapping constructs of mystical experience and quantum change experiences
PT

have also been variously labeled as conversion experiences, religious experiences, peak experiences,
CE

transcendental experiences, transforming moments, or epiphanies (e.g. James, 1902; Stace, 1960;

Maslow, 1968; Miller and C’de Baca, 2001). These experiences are scientifically interesting and
AC

important to study because they are sometimes associated with abrupt, substantial, and sustained

changes in behavior and perception. Furthermore, the authoritative sense of interconnectedness that is

a key feature of mystical-type experiences have been proposed by some to be foundational to the

world’s ethical and moral systems (Huxley, 1947; Stace, 1960a; Jones, 2016). Despite their apparent

importance, the unpredictability and low probability of “naturally occurring” mystical-type and
 ACCEPTED MANUSCRIPT

insightful-type experiences, whether they occur in religious or nonreligious contexts, has made them

inherently difficult to study in controlled empirical research.

Because much more research has focused on mystical experiences than quantum change

experiences and relatively little research has assessed insightful-type experiences per se, our emphasis

will be primarily on mystical-type experiences. Our summary below draws heavily on a detailed recent

T
review of classic psychedelics and mystical experience (Barrett and Griffiths, 2017).

IP
CR
The most definitive review of mystical experience was compiled by Stace (1960a) who identified

and distilled descriptions of mystical experiences from a variety of sources. Stace hypothesized that

US
mystical experiences have a common core of phenomenological features that are independent from the

interpretation of those experiences. He proposed that a defining feature of the mystical experience is a
AN
sense of unity, or the experience of becoming one with all that exists. He distinguished between
M

introvertive (internal) and extrovertive (external) variants of unity experiences. In addition to Internal

unity and External unity, Stace described several other dimensions of mystical experience: Sacredness -
ED

a sense that what is encountered is holy or sacred; Noetic quality - the experience is imbued with an
PT

aspect of meaning and a sense of encountering ultimate reality that is more real than usual everyday

reality; Positive mood - joy, ecstasy, blessedness, peace, tenderness, gentleness, tranquility, awe;
CE

Transcendence of time and space - that notions of time and space have no meaning during the

experience; and Ineffability - the experience is difficult to put into words. Stace also cited Paradoxicality
AC

(the coexistence of mutually exclusive states or concepts) as a dimension of mystical experience,

however the validity of that dimension has been questioned in subsequent empirical studies of mystical

experience (Hood, 1975; MacLean et al., 2012).

Mystical experiences have been an active area of investigation in the experimental psychology

literature, particularly within the psychology of religion (Hood 2009). The Mysticism Scale, a
 ACCEPTED MANUSCRIPT

psychometric instrument that codifies the descriptive definition of mystical experience provided by

Stace (Hood 1975; Hood et al. 2001) has been used extensively in this research.

4.1 Psilocybin and mystical experiences in healthy volunteers

The long historical use of naturally-occurring classic psychedelics by indigenous populations in

ceremonial contexts is well documented (Westermeyer 1988; Wasson et al. 1978; Schultes et al. 2001).

T
IP
Psychoactive plants and fungi for which there is substantive knowledge of ceremonial use include

CR
peyote, ayahuasca, and psilocybin mushrooms. The reasons for such ceremonial use included use for

medicinal and divination purposes, but a prominent goal of ceremonial consumption of classic

US
psychedelics has also likely been to occasion mystical-type experiences (Roberts 2001).
AN
The first experimental study to investigate the effects of a classic psychedelic on mystical

experience was the so-called Good Friday experiment conducted by Walter Pahnke in 1962. The study
M

involved administration of either 30 mg psilocybin (n = 10) or 200 mg nicotinic acid (n = 10) to seminary
ED

students in a private chapel on Good Friday during the broadcast of the traditional Good Friday religious

service (Pahnke, 1963). After the experience, and at a 6-month follow-up, participants completed a
PT

questionnaire that assessed dimensions of mystical experience that were based on the model of

mystical experience developed by Stace (1960a). The mean percentage of maximal possible score for the
CE

first 6 Stace dimensions of mystical experience (listed above) was 64.1% among subjects who received
AC

psilocybin (Pahnke 1967b). Pahnke's criteria for a “complete” mystical experience are somewhat

unclear, but it appears he considered such experiences as being defined by ratings of at least 60% of the

total possible score (Pahnke 1969) or at least 60% to 70% for each of 9 dimensions (unity, sacredness,

positive mood, transcendence of time and space, ineffability, and paradoxicality, transiency, and

persisting positive changes in attitudes and behaviors) (Pahnke 1967a). By this criterion, "3 or 4 of the

ten psilocybin subjects reached the 60% to 70% level of completeness, whereas none of the control
 ACCEPTED MANUSCRIPT

subjects did" (Pahnke, 1967a). In a 25-year follow-up to the Good Friday experiment, Doblin (1991) was

able to contact 16 of the 20 original participants and collect additional retrospective ratings. That study

found little change between the 6-month retrospective ratings and the 25-year retrospective ratings of

mystical experience.

While groundbreaking, the Good Friday experiment had significant limitations, including limited

T
generality due to the highly selective demographics of the participants (seminary students), conduct of

IP
the study in a group setting that allowed interactions among participants (thus resulting in

CR
nonindependence of individual subject data), explicit instructions to participants that some would and

US
some would not receive psilocybin (thus creating powerful expectancy effects), and the fact that half of

the researchers present during the study also received psilocybin. Not surprisingly, under these
AN
conditions, the blind was broken shortly after drug administration, which likely contributed to the

assessed differences between groups (Doblin 1991; Wulff 1991; Smith 2000).
M

In a replication and extension of the Good Friday experiment, a double-blind crossover

ED

comparative pharmacology study was conducted of psilocybin (30 mg/70 kg) and methylphenidate (40
PT

mg/70 kg) administered in separate sessions to each of 36 participants individually, with at least two

months between sessions (Griffiths et al. 2006, 2008). Participants in this study were well educated,
CE

psychiatrically and medically healthy, had no prior psychedelic use, and represented a more general

sample of the population than those used in the Good Friday experiment. The study reduced expectancy
AC

and group confounding effects by studying participants without personal histories of psychedelic use, by

studying only a single participant at a time, and by using an experimental design and instructions that

obscured the range of drug conditions that would be administered as well as the total possible number

of sessions. The study also utilized a better control condition (methylphenidate) than the Good Friday

experiment (nicotinic acid). Methylphenidate and psilocybin can both induce strong subjective effects

with some similarities, and with a reasonably similar time course. Nicotinic acid, in contrast, has a
 ACCEPTED MANUSCRIPT

relatively short time course and a profile of subjective effects that is very different from psilocybin.

Finally, in addition to using a revised and updated version of the mystical experience questionnaire used

in the Good Friday experiment, this study used two psychometrically validated questionnaires that

assessed mystical and spiritual effects (the Hood Mysticism Scale and the Spiritual Transcendence Scale)

as well as ratings of changes in participant’s attitudes and behavior by community observers (family

T
members and friends of participants).

IP
In this and most subsequent studies from the Johns Hopkins laboratory, a 4-factor, 30-item

CR
Mystical Experience Questionnaire (MEQ30) was used. The factor structure of the MEQ30 is described in

US
the text box. The MEQ30 is a shortened and psychometrically refined version of the original 43-item

Mystical Experience Questionnaire (MEQ43) presented in the appendix to Griffiths et al., 2006. The
AN
MEQ30 was validated in both retrospective accounts of mystical experiences with psilocybin (MacLean

et al. 2012) and in prospective, experimental laboratory studies with psilocybin (Barrett et al. 2015). The
M

mean percentage of maximum total possible score for the Griffiths et al., 2006 study was 78% and 33%
ED

immediately after psilocybin and methylphenidate, respectively, and 76% 14 months after psilocybin

(Barrett et al. 2015, appendix 3). Using scoring criteria for having a “complete" mystical experiences that
PT

were analogous but more precise than those used in the Good Friday study (i.e. ≥ 60 percent of the total
CE

possible score on each of four factors of the MEQ30), 61% of participants were scored as having had

complete mystical experiences both at the end of the psilocybin session and at 14-month follow-up
AC

(Barrett et al., 2015, appendix 3). In contrast, 7% of participants met criteria for a complete mystical

experience at the end of the methylphenidate session. Two months after the session, most participants

rated their psilocybin session as among the top five (71%) or single most spiritually significant

experience of their lives, compared to 8% of participants after methylphenidate (Griffiths et al., 2006).

Ratings of positive attitudes about life and self, positive mood, positive behaviors, and positive social

effects 2 months after psilocybin sessions were significantly greater than those provided 2 months after
 ACCEPTED MANUSCRIPT

methylphenidate sessions. Further, community observer ratings showed small but significant changes in

participants’ positive attitudes and behaviors 2 months after the psilocybin sessions, but no changes

were found 2 months after methylphenidate sessions. In a 14-month follow-up report, 67% of

participants rated their psilocybin session as among the top five most spiritually significant experiences

of their lives, and 58% of participants rated their psilocybin session as among the top five most

T
personally meaningful experiences of their lives (Griffiths et al. 2008). Ratings of positive behavior,

IP
mood, attitude, and social changes associated with the psilocybin session at the 14-month follow-up

CR
were not significantly different from those provided 2 months post session. Correlation and regression

analyses indicated a central role of mystical experience assessed on the session day, but not intensity of

US
psilocybin experience, in predicting the high ratings of spiritual significance and personal meaning
AN
assessed at 14 months (Griffiths et al. 2008).

An extension of this line of research utilized a double-blind placebo-controlled design that assessed
M

the effects of placebo and a range of psilocybin doses (Griffiths et al., 2011). Eighteen volunteers, with
ED

demographics generally similar to those in the previous study, participated. Volunteers received 5, 10,

20, and 30 mg/70 kg of psilocybin in separate sessions with at least one month between each session
PT

and a placebo session randomly placed within the sequence. Mystical experience was an increasing
CE

function of psilocybin dose (Griffiths et al., 2011; Barrett et al., 2015, appendix 3). The mean percentage

of maximum total possible score on the MEQ30 on session days was 23%, 47%, 52%, 70%, and 77% after
AC

placebo and 5, 10, 20, and 30 mg/70 kg psilocybin. This score for 30 mg/70 kg at 14 months was 81%.

The percentage of participants meeting criteria for a “complete” mystical experience on session days

was 6%, 11%, 17%, 61%, and 67%, for placebo and the four doses of psilocybin, respectively. This

percentage for 30 mg/70 kg at 14 months was 78%. Ratings 1 month after sessions of the spiritual

significance of the experience and positive behavior change attributed to the experience also increased

with dose. Eighty-three percent of participants rated the session experiences after 20 and/or 30 mg/70
 ACCEPTED MANUSCRIPT

kg as among the five most spiritually significant experiences of their life; 61% also rated at least one of

these as the single most spiritually significant experience of their life. Likewise, 1 month follow-up

ratings of positive attitudes about life and self, positive behavior, positive social effects, and increased

spirituality generally increased as a function of psilocybin dose. One month follow-up ratings after the

20 or 30 mg/70 kg sessions did not differ from follow-up ratings 14 months after study completion.

T
Finally, compared to pre-study ratings, community observers rated significant positive change in the

IP
attitudes and behaviors of participants 3 to 4 weeks after the final session and 14 months after the final

CR
session.

US
A further extension of this research explored the role of psilocybin-occasioned mystical experience

in combination with meditation and other spiritual practices to produce enduring changes in trait
AN
measures of prosocial attitudes and behaviors (Griffiths et al., 2018). Participants were medically

healthy and had relatively low rates of meditation and spiritual practices (e.g., 31% reported some level
M

of current meditation; mean frequency of meditation for all participants was 1.1 times per month).
ED

Participants were randomized to one of three groups (n = 25 each): 1. very-low-dose (1 mg/70kg on

sessions 1 and 2) with moderate-level (“standard”) support for spiritual-practice (LD-SS); 2. high-dose
PT

(20 and 30 mg/70kg on sessions 1 and 2, respectively) with standard support (HD-SS); and 3. high-dose
CE

psilocybin (20 and 30 mg/70kg on sessions 1 and 2, respectively) with high support for spiritual-practice

(HD-HS). The standard spiritual support conditions consisted of 7 hours of individual meetings over the
AC

study, while the high support condition consisted of 35 hours of individual and group meetings.

Meetings consisted of discussion and encouragement for daily meditation, spiritual awareness, and

journaling practices. Psilocybin was administered double-blind and instructions to participants/staff

minimized expectancy confounds. The proportion of participants who met criteria for having had a

“complete” mystical experience on the MEQ30 immediately after sessions 1 and 2, respectively, were

0% and 4% (LD-SS), 48% and 50% (HD-SS), and 44% and 52% (HD-HS). Overall, 4%, 61%, and 64% of
 ACCEPTED MANUSCRIPT

participants in the LD-SS, HD-SS, and HD-HS groups had “complete” mystical experiences at either or

both sessions 1 and 2. The mean percentage of maximum total possible score on the MEQ30 collapsed

across both sessions was 19%, 66% and 74%, respectively for the LD-SS, HD-SS), HD-HS groups. At 6

months, compared to LD-SS, both high-dose groups showed large significant positive changes on

longitudinal measures of interpersonal closeness, gratitude, life meaning/purpose, forgiveness, death

T
transcendence, daily spiritual experiences, religious faith and coping, and community-observer ratings.

IP
Hierarchical regression analysis was used to examine the relationship of mystical experience (MEQ30

CR
scores) and specific spiritual practices to the various outcome measures that showed between group

differences at 6 months. This analysis indicated that both mystical experience and spiritual practices

US
contribute to positive outcomes, with mystical experience making a substantially greater contribution.
AN
The fact that the measure of mystical experience preceded the assessment of outcome measures by 4-5

months strengthens the interpretation that mystical experience and/or its neurophysiological or other
M

correlates are likely determinants of the enduring positive attitudinal, dispositional, and behavioral
ED

effects of psilocybin when administered under spiritually supported conditions.

Although the foregoing study of psilocybin combined with spiritual practices showed robust
PT

enduring changes in various trait measures suggesting healthy psychological functioning, the study
CE

showed equivocal effects on the personality domain of Openness. Specifically, the study showed that

Openness increased from screening to 6 months in the HD-HS group but not in the HD-SS or LD-SS
AC

groups. However, there were no between-group differences in Openness at 6 months. Further analyses

of these data did not show significant relationships between several measures of mystical-type

experience and changes in Openness. These findings contrast with the results from a previous analysis

that showed that psilocybin-occasioned mystical experience was associated with increases in Openness

from screening to 1–2 months and to 14 months after psilocybin (MacLean et al., 2011). Increases in

Openness have been shown 2 weeks after administration of LSD in healthy individuals (Lebedev et al.,
 ACCEPTED MANUSCRIPT

2016). The failure to observe significant increases in Openness in the most recent study might be

attributable to engagement in the program of spiritual practices or to some other aspect of the study

design.

In a recent study of psilocybin and mystical experience from Johns Hopkins, Carbonaro et al. (2018)

examined single, acute oral doses of psilocybin (10, 20, 30 mg/70 kg), dextromethorphan (400 mg/70

T
kg), and placebo under double-blind conditions to 20 participants with histories of psychedelic use.

IP
Dextromethorphan, a N-methyl-D-aspartate (NMDA) receptor antagonist, was used as a comparator in

CR
this study because it is sometimes used at high doses (e.g., ≥300 mg) as an atypical hallucinogen or

US
psychedelic (Banken and Foster, 2008; Morris and Wallach, 2014). Volunteer preparation and session

support were similar to previous studies. The mean percentage of maximum total possible score on the
AN
MEQ30 at the end of sessions increased with psilocybin dose and was significantly higher after 10, 20,

and 30 mg/70 kg psilocybin (39%, 53% and 63%, respectively) than after placebo (8%). Furthermore, the
M

mean percentage of maximum total possible score on the MEQ30 at the end of sessions was
ED

significantly higher after 20 and 30 mg/70 kg psilocybin (53% and 63%, respectively) than after DXM

(40%). The proportion of volunteers who met a priori criteria for having had a “complete” mystical
PT

experience on the MEQ30 was: 0%, 0%, 20%, 40%, and 0% after placebo, 10, 20, and 30 mg/70 kg
CE

psilocybin, and DXM, respectively. The incidence of complete mystical experience after the 30 mg/70 kg

psilocybin dose was significantly greater than after both placebo and DXM.
AC

Barrett and Griffiths (2017) conducted a further analysis of psilocybin-occasioned mystical

experience in 119 healthy volunteers by collapsing data at 30 mg/70 kg psilocybin across three studies

(Griffiths et al., 2006, 2011, 2018). On the MEQ30 completed on session days, 57% of participants met

criteria for a "complete" mystical experience, with the mean percentage of maximum total possible

score being 73%. In retrospective follow-up ratings, most participants rated this session experience in
 ACCEPTED MANUSCRIPT

the top five most personally meaningful (66%) or spiritually significant (68%) in their lives, with 70%

rating moderate or greater positive behavior change that they attributed to the session experience.

4.2 Psilocybin and mystical experiences in therapeutic trials

As previously detailed in sections 2.1 and 2.3, four studies have assessed psilocybin-occasioned

mystical experience in the context of therapeutic trials. All four of these studies showed that psilocybin

T
IP
produced significant increases in mystical experience scores and, consistent with the previous studies

CR
showing associations between mystical experience and enduring positive outcomes (Griffiths et al.,

2008, 2011), these therapeutic studies suggest similar associations with therapeutic outcomes.

US
As described in section 2.1, two studies showed that psilocybin produces substantial and enduring
AN
decreases in symptoms of anxiety and depression among patients with a life-threatening cancer

diagnosis (Griffiths et al., 2016; Ross et al., 2016). For the Griffiths et al. (2016) study, mean percentage
M

of maximum total possible score on the MEQ30 was significantly higher immediately after the high dose
ED

64% than after the lower dose (27%). These scores after the first session were significantly correlated

with most of the enduring changes in therapeutic outcome measures 5 weeks later. For most measures,
PT

this relationship continued to be significant when the intensity of overall psilocybin effect was controlled

for in a partial correlation analysis, suggesting that mystical-type experience per se has an important
CE

role apart from overall intensity of drug effect. Furthermore, analysis suggested that mystical-type
AC

experience was a mediator in positive therapeutic response. Similar to these results, the Ross et al.

(2016) study found that the mean percentage of maximum possible total score on the MEQ30 was

higher immediately after psilocybin than after niacin (estimated from figures as approximately 66% and

10%, respectively), and correlation analysis controlling for intensity of drug effect and a mediation

analysis suggested that mystical experience was a mediator of the therapeutic effects.
 ACCEPTED MANUSCRIPT

As described in section 2.3, two open-label pilot studies of psilocybin in the treatment of substance

dependence have reported data consistent with these findings. In the smoking cessation study (Johnson

et al., 2014), mystical experience was assessed with the MEQ43. Nine of 15 participants (60%) had a

“complete” mystical experience during one or more psilocybin sessions. In 10 of 13 (77%) participants,

“complete” mystical experiences occurred during high dose (30 mg/70kg) sessions. Across all psilocybin

T
sessions the mean percentage of maximum total possible score on the MEQ43 was 63%. Significant

IP
correlations between mean MEQ43 total scores and smoking craving change scores (r = -.65) and urine

CR
cotinine (r = -.56) were found at the 6-month follow-up. Finally, those participants who showed stronger

mystical experiences on psilocybin session were more likely to be successful in quitting smoking (Garcia-

US
Romeu et al., 2014). In the pilot study of alcohol dependence (Bogenschutz et al., 2015), the mean
AN
percentage of maximum total possible score on the MEQ43 was 47% (n=10) and 39% (n=6) on session 1

(21 mg/70 kg) and 2 (28 mg/70 kg) respectively. Positive change in drinking was significantly correlated
M

with MEQ43 as well as with other measures of intensity of psilocybin effect.

ED

4.3 Lysergic acid diethylamide (LSD) and mystical experiences

PT

The effects of LSD on mystical experience are of particular interest, as LSD is another classic

serotonergically mediated psychedelic. Liechti et al., (2017) present results on the effects of LSD in two
CE

studies: 1. a double-blind cross-over study 16 in healthy volunteers comparing placebo and 200 ug LSD;

and 2. a double-blind cross-over study in 12 anxious patients with life-threatening diseases comparing
AC

200 ug LSD to a low LSD dose (25 ug)(Gasser et al., 2014). Estimated mean percentage of maximum total

possible score on the MEQ30 was 61% and 2% for LSD and placebo respectively in the healthy

volunteers, and 50% and 5% respectively in the patients. The percentage of participants meeting criteria

for a "complete" mystical experience was 12.5% in the healthy volunteers and 17% in the patients.

Whether this seemingly lower rate of mystical experience after LSD than psilocybin reflects

pharmacodynamic differences between these drugs, the use of a relatively lower dose of LSD than
 ACCEPTED MANUSCRIPT

psilocybin, and/or differences between the studies in set, setting, or participant characteristics is

unknown. Future research should directly compare LSD and psilocybin within subjects, ideally using

procedures to minimize expectancy effects.

5. Brain network changes as mechanisms underlying classic psychedelic effects

The brain is composed of many levels of embedded complex systems. These systems have

T
IP
modularity, in the sense that individual nodes or brain regions that subserve certain individual functions

CR
(such as representing line orientation, brightness, and hue of a visual stimulus) are segregated from

nodes that serve other functions (such as nodes that represent sounds or bodily sensations, or nodes

US
that represent tactile sensation or motor movement). The embedded complex systems of the brain also

require integration (i.e. connection and communication) between nodes in order to support efficient
AN
communication between modules that underlie complex processes (such as hand-eye coordination). A
M

balance of modularity and efficient integration is necessary to support normal waking consciousness.
ED

Resting-state functional MRI connectivity analyses have shown that, under normal conditions,

communication between areas of the brain is organized into stable networks (Yeo et al., 2011; Power et
PT

al., 2011; Doucet et al., 2011) that demonstrate both modularity and integration (Sporns, 2011).

Commonly identified networks underlie sensory, motor, and cognitive processes (Smith et al., 2009,
CE

Shirer et al., 2012) and have features that are unique between individuals and stable enough within-
AC

individuals that separate scans from the same individual can be identified with very high accuracy (99%

or greater) in a large database of scans (‘connectome fingerprinting’; Finn et al., 2015; Airan et al.,

2016). In such fingerprinting analyses, connectivity among higher-order brain regions involved in self-

referential processing and attention show the greatest inter-individual differences and typically

contribute most to identifying an individual’s connectivity pattern within a large database of

 ACCEPTED MANUSCRIPT

connectivity patterns (Finn et al., 2015; Airan et al., 2016). Individual differences in the connectivity of

these networks may in a sense constitute an individual’s ‘neural identity’.

While typically observed brain networks are reliably found under normal circumstances in

resting-state functional connectivity data, activity and correlation within (modularity) and between

(integration) these networks has been shown to decrease during the acute effects of psilocybin (Carhart-

T
Harris et al., 2012; Muthukumaraswamy et al., 2013), ayahuasca (Palhano-Fontes et al., 2015), and LSD

IP
(Carhart-Harris et al., 2016, Speth et al., 2016). In particular, activity and connectivity of brain regions

CR
crucial to self-referential processing (including regions of the default mode network, or DMN, such as

US
the posterior cingulate cortex) are most strongly impacted by classic psychedelics (Carhart-Harris et al.,

2012, 2016; Palhano-Fontes et al., 2015). Decoupling and decreased modularity of typically observed
AN
large-scale/long-range brain networks has been shown (Lebedev et al., 2015), and during acute drug

effects, the brain reorganizes into new, local range networks (Petri et al., 2014). An increased number of
M

distinct patterns in the brain compared to normal waking consciousness has been demonstrated with
ED

both psilocybin (Tagliazucchi et al., 2014) and LSD (Schartner er al., 2017), and the overall connectivity

and global integration of the brain was shown to increase in a manner that was correlated with
PT

subjective reports of “ego dissolution” during LSD1 (Tagliazucchi et al., 2016). Changes in the brain
CE

during the acute effects of classic psychedelics have more generally been associated with subjective

effects including “dissolution of the self or ego” (Carhart-Harris et al., 2014) and mystical-type (Barrett
AC

and Griffiths, 2017) or spiritual (Kometer et al., 2015) experiences that may have therapeutic value

(Garcia-Romeu et al., 2014; Griffiths et al., 2016; Ross et al., 2016; Barrett and Griffiths, 2017).

Overall, the acute effects of classic psychedelics on measures of systems-level neural functioning

have included a decrease in both modularity and integration of commonly identified brain networks,

1
These reports were collected by asking volunteers to respond to questionnaire items such as “I experienced a
dissolving of my self or ego” though it is not clear that any further definition was given to volunteers for the terms
“self” or “ego.”
 ACCEPTED MANUSCRIPT

and a reconfiguration of communication in the brain. Increased brain entropy2, which is a physical

measure of increased randomness or uncertainty within a system, has been proposed as a mechanism

of acute altered states of consciousness with psilocybin (Carhart-Harris et al., 2014) and LSD (Lebedev et

al., 2016; Shartner et al., 2017). While this large-scale principle may be at work in the brain during an

experience with a classic psychedelic, it does not explain the formation of new, local networks in the

T
brain (Petri et al., 2014) or the observed increases in the number of distinct patterns in the brain

IP
compared to normal waking consciousness (Tagliazucchi et al., 2014). An account of temporary and

CR
structured reconfiguration of the brain, rather than only increased randomness in the system (entropy),

is more consistent with reported data.

US
Electro- and magneto-cortical studies have demonstrated a broadband reduction of oscillatory
AN
power (i.e., decreased brainwave amplitude), and especially low-frequency oscillations (alpha band), by

psilocybin (Kometer et al., 2013, 2015, Muthukumaraswamy et al., 2013) and ayahuasca (Riba et al.,
M

2002, 2004, Valle et al., 2016). While oscillations in the same frequency band can serve different
ED

functions in different regions of the brain (e.g. theta band oscillations in hippocampus may not serve the

same function as theta band oscillations in the thalamus), lower-frequency oscillations are generally
PT

known to modulate information in higher frequencies (Buzsaki et al., 2013). In particular, alpha band
CE

synchrony modulates attention and information selection processes that are subserved in higher

frequency bands (e.g. gamma) (Klimesch, 2012), and serves a specific role in modulating top-down
AC

cortical control, which allows for maintenance of integration and modularity of brain networks through

2
Entropy as utilized by Carhart-Harris et al. (2014) was formally calculated as the Shannon entropy of intra-brain-
network synchrony – more specifically, the negative logarithm of the probability distribution of the variance in the
synchrony between nine canonical brain networks. To the degree that only a single event within a probability
distribution of a function occurs with high probability, the probability distribution will not be flat, and the
frequency of events generated from that distribution will be far less random (or far more predictable) than a
probability distribution in which all events occur with equal probability and from which any given event will be
nearly unpredictable (or generated from a stochastic process). The former case is a case with very low entropy,
and the latter case is a case with very high entropy. Thus, entropy can be used as a formal measure of the
randomness or uncertainty within a system.
 ACCEPTED MANUSCRIPT

altering the transient coupling between and among networks of brain areas (Bazanova et al., 2014).

Synchronization of alpha oscillations between parahippocampus, retrosplenial (near posterior cingulate

cortex or PCC), and lateral orbitofrontal cortices (regions associated with the DMN) is associated with

psilocybin-induced spiritual experience (Kometer et al., 2015), and decreases in alpha power in the PCC

are associated with psilocybin-induced “disintegration of the self or ego” (Carhart-Harris et al., 2014).

T
Thus, decreased alpha synchrony in the brain may be an electrocortical mechanism resulting in

IP
decreased integration and modularity of typically observed brain networks, and may be critical to the

CR
formation of temporary, new, local and stable networks (Petri et al.,. 2014) and distinct patterns of

activity (Tagliazucchi et al., 2014) that are observed during acute classic psychedelic drug effects.

US
While fMRI, EEG, and MEG measures have primarily shown classic psychedelics to produce an
AN
overall reduction in activity and connectivity in the brain, early molecular imaging studies, including PET

and SPECT demonstrated various signs of increased brain activity during acute effects of psilocybin
M

(Vollenweider et al., 1997, Vollenweider et al., 1999, Gouzoulis-Mayfrank et al., 1999b) and mescaline
ED

(Hermle et al., 1992). Along with reports of decreased measures of metabolic activity in subcortical (e.g.

thalamus) and posterior (e.g. parietal, occipital, temporal) regions, these molecular imaging studies
PT

found a relative increase in activity of frontal brain regions in particular to be a prominent acute neural
CE

effect of classic psychedelic drugs. Evidence suggesting a resolution of this discrepancy in the literature

was recently provided (Lewis et al., 2017), showing that an overall decrease in brain activity is found
AC

when assessing the effects of classic psychedelics on global or absolute cerebral blood flow, and findings

of hyperfrontality are recovered when calculating relative cerebral blood flow, which controls for global

changes in blood flow. The implication of this finding is that, while overall blood flow may decrease in

the brain during the effects of classic psychedelics, these blood flow decreases are not as substantial in

prefrontal brain regions in that some frontal regions may be partially spared in relation to posterior

brain regions. However, it has yet to be determined whether these relative differences in activity
 ACCEPTED MANUSCRIPT

observed in early PET studies relate to increases or decreases in modularity or integration of brain

networks. Also, it is as yet unclear whether overall decreases in blood flow, or the relative balance of

frontal activity relative to activity in other brain regions, is more directly responsible for acute effects of

classic psychedelics. It is likely that both processes contribute to the unique character of experiences

occasioned by the administration of classic psychedelics.

T
5.1 Relation of neural effects to therapeutic effects

IP
CR
The DMN consists primarily of the posterior cingulate cortex (PCC), medial prefrontal cortex

(MPFC), and lateral parietal cortex (LPC). The PCC is involved with internally-directed cognition (Leech

US
and Sharp, 2014), the MPFC (and adjacent region of the subgenual anterior cingulate, or sgACC) is

implicated in rumination (Cooney et al., 2010; Berman et al., 2011; Kucyi et al., 2014), autobiographical
AN
memory recall (Svoboda et al., 2006), self-related judgements and theory of mind processes (Gilbert et
M

al., 2006; Denny et al., 2012), and the LPC has been implicated in a number of processes, including

empathy (Kubit and Jack, 2013) and coding a sense of self in spatial cognition (Amorapanth et al., 2009).
ED

Impaired connectivity of DMN brain regions to non-DMN brain regions in major depression is associated
PT

with greater disorder severity (Seminowicz et al., 2004), and abnormally high connectivity among

regions of the DMN and abnormally low connectivity between DMN and executive networks have been
CE

implicated in the pathophysiology of major depression (Leibenluft and Pine, 2013). Lower connectivity

within the DMN, greater connectivity of sgACC to DMN regions, greater connectivity of sgACC to
AC

executive network regions, and greater connectivity within the executive network predict better

medication treatment response (Dichter et al., 2015). Neuropathological, molecular imaging, and

targeted brain stimulation treatment studies demonstrate that dysregulation of an extended network of

brain regions in major depression may originate in abnormalities in medial frontal regions of the DMN

(Price and Drevets, 2012). DMN connectivity is normalized along with depressive symptoms after

transcranial magnetic stimulation (TMS) of the dorsolateral prefrontal cortex, deep brain stimulation of
 ACCEPTED MANUSCRIPT

the subgenual anterior cingulate (Mayberg et al., 2005; Lozano et al., 2012), and electroconvulsive

therapy (Cano et al., 2016). This demonstrates a functional relationship between DMN and frontal

cortex function and depression. It may be that acute reconfiguration of brain networks during the

effects of classic psychedelics, which strongly impact DMN and frontal brain activity and connectivity,

lead to lasting alterations in these networks that represent a systems-level mechanism by which classic

T
psychedelics may have efficacy in treating depression. However, the enduring effects of classic

IP
psychedelics on the brain have not yet been demonstrated.

CR
A growing body of evidence suggests that traditional antidepressants, as well as novel

US
medications effective in treatment-resistant depression, exert their therapeutic efficacy via the indirect,

downstream action of glutamate (Cryan and O'Leary, 2010; Deutschenbaur et al., 2016; Duman et al.,
AN
2012; Duman and Voleti, 2012; Dutta et al., 2015; Sanacora et al., 2008; Skolnick et al., 2009, Krystal et

al., 2013). Depressed patients have lower glutamate/glutamine levels at baseline (Hasler et al., 2011)
M

and reduced baseline glutamate levels are positively correlated with subsequent antidepressant
ED

response to ketamine (Salvadore et al., 2012). Biophysical computational models have implicated

specific dysfunction of the glutamatergic activity in medial frontal regions of the DMN as the mechanism
PT

that underlies impairments in functional connectivity of this region in major depressive disorder
CE

(Ramirez-Mahaluf et al., 2015). Recent MRS studies demonstrate that psilocybin decreased BOLD

activity and increased glutamate concentration in healthy individuals in the anterior cingulate cortex
AC

(ACC) (Preller et al., 2016), in a manner consistent with therapeutic response in the ACC in patients who

are being treated for depression. Thus, a molecular mechanism of action of classic psychedelics may be

to alter the connectivity and activity of brain regions implicated in the pathophysiology of depression by

altering glutamatergic functioning in these regions (Vollenweider and Kometer, 2010).

If a hyperactive and hyperconnected DMN underlies depression, a hypoactive and

hypoconnected DMN may underlie addiction. The cycle of addiction is now understood to relate to a
 ACCEPTED MANUSCRIPT

disruption of the balance between reward and limbic brain circuitry and top-down cortical control

(including control from prefrontal/executive networks and the DMN) (Volkow et al, 2016). DMN and

prefrontal/executive network connectivity is decreased in chronic cocaine (Gu et al., 2010), nicotine

(Cole et al., 2010), and heroin (Jiang et al., 2011) users. The typically observed balance between activity

and connectivity of DMN and prefrontal/executive networks is also altered during craving in volunteers

T
with substance use disorders (Lerman et al., 2014, Sutherland et al., 2012, Lu et al., 2014). Reduction of

IP
craving and withdrawal symptoms may result from normalization of these abnormal connectivity

CR
patterns (Cole et al., 2010). Similar to depression, acute and/or lasting reconfiguration of brain

networks, in particular prefrontal and DMN regions, by classic psychedelics may represent systems-level

US
mechanisms supporting therapeutic effects of classic psychedelics.
AN
5.2 Insights into the biological basis of consciousness
M

Neurobiological studies of the effects of psychedelics have yielded insights that may be relevant

to understanding the biological basis of consciousness. It is notable that conscious awareness can be
ED

maintained during psychedelic experiences, yet this conscious awareness appears to be vastly different
PT

than normal waking consciousness. During psychedelic experiences, the underlying functional

connectivity of the brain is also vastly altered. This suggests that there may be a relationship between
CE

the changes in functional brain connectivity during psychedelic experiences and the changes in

consciousness that are encountered during psychedelic experiences. Communication within and
AC

between networks of brain regions may constitute a biological carrier signal on which awareness and a

sense of self emerges, but conscious awareness need not be constrained by the typical patterns of

communication between and within brain networks. Thus, not only does the brain show plasticity, but

we are learning clearly that discrete interventions that vastly alter brain communication can be achieved

with psychedelics, and these alterations may be the neurobiological basis of quantum change observed

behaviorally after administration of psychedelics

 ACCEPTED MANUSCRIPT

6. Conclusions

Contemporary therapeutic research with classic psychedelics has shown promising effects for

both cancer-related psychological distress, and addiction to both tobacco and alcohol. In addition, basic

scientific studies using classic psychedelics have led to numerous advances in the experimental study of

mystical experiences and the study of classic psychedelic mechanisms of action. Perhaps most

T
importantly, neurobiological studies of the effects of classic psychedelics have yielded insights into the

IP
biological basis of consciousness. Specifically, these studies collectively suggest the possibility that the

CR
pattern and structure of communication between brain networks constitutes the neurobiological basis

US
of consciousness, such that alterations of consciousness are driven by alterations of communication

between brain regions. Interestingly, large-scale epidemiological studies of naturalistic classic

AN
psychedelic use are consistent with contemporary clinical research, and point to intriguing future trends,

namely the application of classic psychedelics in forensic settings.

M

Promising recent results have been published for cancer-related psychological distress, using
ED

both psilocybin and LSD, replicating one major focus of the earlier era of classic psychedelic research.
PT

Many of these studies have shown such findings using rigorous double-blind procedures that vary in

methods. Consistent signals of efficacy in the face of such variations suggest a robust clinical response.
CE

In the United States, if future phase 3 research supports these preliminary findings showing the safety

and efficacy of psilocybin in the treatment of cancer-related psychological distress, non-research

AC

therapeutic use of psilocybin, under appropriately restricted safeguards adhering to strict safety

standards (Johnson et al., 2008), may eventually warrant regulatory approval. Additionally, pilot

research on treatment-resistant depression also shows preliminary promise in response to classic

psychedelic treatment outside of the context of cancer. If such findings are demonstrated in randomized

studies, classic psychedelics may be poised as breakthrough medications for the leading cause of

worldwide disability, affecting over 300 million human beings (World Health Organization, 2017).
 ACCEPTED MANUSCRIPT

Although the clinical research agenda on addictions is at a lesser stage of development in comparison to

cancer-related psychological distress, with only open-label pilot studies having been completed thus far

in contemporary research (Bogenschutz et al., 2015; Johnson et al., 2014), if randomized clinical trials

continue to suggest safety and efficacy, clinical approval of the use of psilocybin for the treatment of

specific addiction may also be on the horizon.

T
If safety and efficacy are sufficiently demonstrated to warrant approved therapeutic use of one

IP
classic psychedelic (e.g., psilocybin, LSD), this would suggest the potential therapeutic potential of

CR
additional compounds of the same class. In the typical clinical development of other drug classes (e.g.,

US
benzodiazepines), a seminal compound of the class is identified and developed for therapeutic use (e.g.,

chlordiazepoxide), followed by the discovery and therapeutic development of additional compounds of

AN
the class over the subsequent decades. However, the clinical development of classic psychedelics may

be unique, in that hundreds of psychoactive compounds of this class have already been identified (e.g.,
M

Shulgin and Shulgin, 1991; Shulgin and Shulgin, 1997). Therefore, the broad array of classic psychedelic
ED

compounds that have been universally ignored in pharmaceutical drug development may soon

constitute a library of potential therapeutics. They may also help to inform the biological mechanisms of
PT

human consciousness.
CE
AC
 ACCEPTED MANUSCRIPT

Figure 1. Past 12 Months Prevalence of LSD Use among United States high school students, college

students, and young adults by year from 1975-2016(Monitoring the Future)

Figure 2. Past 12 Months Prevalence of Hallucinogens Other than LSD Use among United States high

school students, college students, and young adults by year from 1975-2016(Monitoring the Future)

Figure 3. Weighted Lifetime Prevalence of LSD, Peyote, Mescaline, and Psilocybin Use in the United

T
IP
States population by year from 1985-2015 (National Survey on Drug Use and Health)

CR
Figure 4. Classic Psychedelic-associated Emergency Department visits per 100,000 Drug-related Visits in

United States Hospitals by year from 2004-2011 (Drug Abuse Warning Networks)

US
Figure 5. United States Drug Enforcement Administration Hallucinogen Seizures by year from 1986 to
AN
2014

Figure 6. Self-reported Prevalence of Lifetime Classic and Novel Psychedelic Use, 2013 (Global Drug
M

Survey)
ED
PT
CE
AC
 ACCEPTED MANUSCRIPT

Conflict of Interest Statement

Roland R. Griffiths is on the Board of Directors of the Heffter Research Institute. The authors declare

that there are no other conflicts of interest.

T
Acknowledgments

IP
Support for effort by the authors has been provided by the Heffter Research Institute (MWJ, PSH, RRG)

CR
and National Institute on Drug Abuse grants R01DA003889 (RRG) and R03DA042336 (FSB). We thank

Jefferson Mattingly, Lisa Mitchell, and Jennifer Mejaes for assistance with manuscript preparation.

US
AN
References
M

Abraham, H.D., Aldridge, A.M., & Gogia, P. (1996). The psychopharmacology of hallucinogens.
ED

Neuropsychopharmacology, 14(4), 285-298. doi: 10.1016/0893-133X(95)00136-2

Abuzzahab, F.S., & Anderson, B. J. (1971). A review of LSD treatment in alcoholism. International
PT

Pharmacopsychiatry, 6(4), 223-235.

CE

Airan, R. D., Vogelstein, J. T., Pillai, J. J., Caffo, B., Pekar, J. J., & Sair, H. I. (2016). Factors affecting
AC

characterization and localization of interindividual differences in functional connectivity using

MRI. Human Brain Mapping, 37(5), 1986-1997. doi:10.1002/hbm.23150

Akers, B. P., Ruiz, J. F., Piper, A., & Ruck, C. A. P. (2011). A prehistoric mural in Spain depicting

neurotropic psilocybe mushrooms? Economic Botany, 65(2), 121-128. doi:10.1007/s12231-011-

9152-5

Alexander T. Shulgin. (1997). Tihkal. Berkeley: Transform Press.

 ACCEPTED MANUSCRIPT

Amorapanth, P. X., Widick, P., & Chatterjee, A. (2010). The neural basis for spatial relations. Journal of

Cognitive Neuroscience, 22(8), 1739-1753. doi:10.1162/jocn.2009.21322

Andersen-Hein, G. W. (1963). LSD in the treatment of criminal psychopaths. In Crocket R.W., Sandison

R.A. & Walk A. (Eds.) Hallucinogenic Drugs and their Psychotherapeutic Use (pp. 101-106). London:

H.K. Lewis.

T
IP
Argento, E., Strathdee, S. A., Tupper, K., Braschel, M., Wood, E., & Shannon, K. (2017). Does psychedelic

CR
drug use reduce risk of suicidality? Evidence from a longitudinal community-based cohort of

marginalised women in a Canadian setting. BMJ Open, 7(9), e016025. doi:10.1136/bmjopen-2017-

US
016025 AN
Australian Institute of Health and Welfare. (2014). Australia’s health 2014. Australia’s Health Series No.

14. Cat. no. AUS 178. Canberra: AIHW.

M

Banken, J. A., & Foster, H. (2008). Dextromethorphan. Annals of the New York Academy of
ED

Sciences, 1139, 402-411. doi:10.1196/annals.1432.003

PT

Barbosa, P. C. R., Cazorla, I. M., Giglio, J. S., & Strassman, R. (2009). A six-month prospective evaluation

of personality traits, psychiatric symptoms and quality of life in ayahuasca-naive subjects. Journal of
CE

Psychoactive Drugs, 41(3), 205-212. doi:10.1080/02791072.2009.10400530

AC

Baron, R. M., & Kenny, D. A. (1986). The moderator-mediator variable distinction in social psychological

research: Conceptual, strategic and statistical considerations. Journal of Personality and Social

Psychology, 51, 1173-1182.

Barrett, F. S., & Griffiths, R. R. (2017). Classic hallucinogens and mystical experiences: Phenomenology

and neural correlates. Current Topics in Behavioral Neurosciences, 36, 393-

430. doi:10.1007/7854_2017_474
 ACCEPTED MANUSCRIPT

Barrett, F. S., Johnson, M. W., & Griffiths, R. R. (2015). Validation of the revised mystical experience

questionnaire in experimental sessions with psilocybin. Journal of Psychopharmacology (Oxford,

England), 29(11), 1182-1190. doi:10.1177/0269881115609019

Bazanova, O. M., & Vernon, D. (2014). Interpreting EEG alpha activity. Neuroscience & Biobehavioral

Reviews; Applied Neuroscience: Models, Methods, Theories, Reviews A Society of Applied

T
Neuroscience (SAN) Special Issue, 44, 94-110. doi:10.1016/j.neubiorev.2013.05.007

IP
CR
Berman, M. G., Peltier, S., Nee, D. E., Kross, E., Deldin, P. J., & Jonides, J. (2011). Depression, rumination

and the default network. Social Cognitive and Affective Neuroscience, 6(5), 548-555.

US
doi:10.1093/scan/nsq080 AN
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. Journal of

M

Psychopharmacology (Oxford, England), 29(3), 289-299. doi:10.1177/0269881114565144

ED

Bouso, J. C., González, D., Fondevila, S., Cutchet, M., Fernández, X., Ribeiro Barbosa, P. C., et al. (2012).

Personality, psychopathology, life attitudes and neuropsychological performance among ritual

PT

users of ayahuasca: A longitudinal study. PLoS ONE, 7(8) doi:10.1371/journal.pone.0042421

CE

Bowen, W., Soskin, R., & Chotlos, J. (1970). Lysergic acid diethylamide as a variable in the hospital

treatment of alcoholism: A follow-up study. The Journal of Nervous and Mental Disease, 150(2),
AC

111-118. doi:10.1097/00005053-197002000-00003

Bunzow, J. R., Sonders, M. S., Arttamangkul, S., Harrison, L. M., Zhang, G. E., Quigley, D. I., et al. (2001).

Amphetamine, 3, 4-methylenedioxymethamphetamine, lysergic acid diethylamide, and metabolites

of the catecholamine neurotransmitters are agonists of a rat trace amine receptor. Molecular

pharmacology, 60(6), 1181-1188.

 ACCEPTED MANUSCRIPT

Bruhn, J. G., & Holmstedt, B. (1974). Early peyote research an interdisciplinary study. Economic

Botany, 28(4), 353-390.

Bruhn, J. G., De Smet, P. A., El-Seedi, H. R., & Beck, O. (2002). Mescaline use for 5700 years. Lancet

(London, England), 359(9320), 1866. doi:S0140-6736(02)08701-9 [pii]

Buzsaki, G., Logothetis, N., & Singer, W. (2013). Scaling brain size, keeping timing: Evolutionary

T
IP
preservation of brain rhythms. Neuron, 80(3), 751-764. doi:10.1016/j.neuron.2013.10.002

CR
C’de Baka, & Miller. (2001). Quantum change: When epiphanies and sudden insights transform ordinary

lives. New York: Guilford Press.

US
Cano, M., Cardoner, N., Urretavizcaya, M., Martinez-Zalacain, I., Goldberg, X., Via, E., & Menchon, J. M.
AN
(2016). Modulation of limbic and prefrontal connectivity by electroconvulsive therapy in treatment-

resistant depression: A preliminary study. Brain Stimulation, 9(1), 65-71.

M

doi:10.1016/j.brs.2015.08.016
ED

Carbonaro, T. M., Johnson, M. W., Hurwitz, E., & Griffiths, R. R. (2018) Double-blind comparison of the
PT

two hallucinogens psilocybin and dextromethorphan: Similarities and differences in subjective

experiences. Psychopharmacology (Berlin), 235(2), 521-534. doi: 10.1007/s00213-017-4769-4

CE

Carbonaro, T. M., Bradstreet, M. P., Barrett, F. S., MacLean, K. A., Jesse, R., Johnson, M. W., et al. (2016).
AC

Survey study of challenging experiences after ingesting psilocybin mushrooms: Acute and enduring

positive and negative consequences. Journal of Psychopharmacology (Oxford, England), 30(12),

1268-1278. doi:0269881116662634 [pii]

Carhart-Harris, R. L., Erritzoe, D., Williams, T., Stone, J. M., Reed, L. J., Colasanti, A., et al. (2012). Neural

correlates of the psychedelic state as determined by fMRI studies with psilocybin. Proceedings of
 ACCEPTED MANUSCRIPT

the National Academy of Sciences of the United States of America, 109(6), 2138-2143.

doi:10.1073/pnas.1119598109

Carhart-Harris, R. L., Leech, R., Williams, T. M., Erritzoe, D., Abbasi, N., Bargiotas, T., et al. (2012).

Implications for psychedelic-assisted psychotherapy: Functional magnetic resonance imaging study

with psilocybin. The British Journal of Psychiatry: The Journal of Mental Science, 200(3), 238-244.

T
doi:10.1192/bjp.bp.111.103309

IP
CR
Carhart-Harris, R. L., Leech, R., Hellyer, P. J., Shanahan, M., Feilding, A., Tagliazucchi, E., et al. (2014). The

entropic brain: A theory of conscious states informed by neuroimaging research with psychedelic

US
drugs. Frontiers in Human Neuroscience, 8, 20. doi:10.3389/fnhum.2014.00020
AN
Carhart-Harris, R. L., Muthukumaraswamy, S., Roseman, L., Kaelen, M., Droog, W., Murphy, K., et al.

2016). Neural correlates of the LSD experience revealed by multimodal neuroimaging. Proceedings
M

of the National Academy of Sciences of the United States of America, 113(17), 4853-4858.
ED

doi:10.1073/pnas.1518377113

Carhart-Harris, R. L., Bolstridge, M., Rucker, J., Day, C. M., Erritzoe, D., Kaelen, M., et al. (2016).
PT

Psilocybin with psychological support for treatment-resistant depression: An open-label feasibility

CE

study. The Lancet Psychiatry, 3(7), 619-627. doi:10.1016/S2215-0366(16)30065-7

Carhart-Harris, R. L., Roseman, L., Bolstridge, M., Demetriou, L., Pannekoek, J. N., Wall, M. B., et al.
AC

(2017). Psilocybin for treatment-resistant depression: fMRI-measured brain mechanisms. Scientific

reports, 7(1), 13187.

Carhart-Harris, R. L., Bolstridge, M., Day, C. M. J., Rucker, J., Watts, R., Erritzoe, D. E., et al. (2018).

Psilocybin with psychological support for treatment-resistant depression: six-month follow-

up. Psychopharmacology, 235(2), 399-408.

 ACCEPTED MANUSCRIPT

Carod-Artal, F., & B Vázquez-Cabrera, C. (2006). Mescaline and the San Pedro cactus ritual:

Archaeological and ethnographic evidence in northern Peru. Revista de Neurologia, 42(8), 489-498.

Chwlos, N., Blewett, D. B., Smith, C. M., & Hoffer, A. (1959). Use of d-lysergic acid diethylamide in the

treatment of alcoholism. Quarterly Journal of Studies on Alcohol, 20, 577-590.

Cohen, S. (1960) Lysergic acid diethylamide: side effects and complications. Journal of Nervous and

T
IP
Mental Disease, 130, 30–40.

CR
Cohen, S. (1965). LSD and the anguish of dying. Harper's Magazine, 231(1384), 69-72.

US
Cole, D. M., Beckmann, C. F., Long, C. J., Matthews, P. M., Durcan, M. J., & Beaver, J. D. (2010). Nicotine

replacement in abstinent smokers improves cognitive withdrawal symptoms with modulation of

AN
resting brain network dynamics. NeuroImage, 52(2), 590-599.

doi:10.1016/j.neuroimage.2010.04.251
M

Cooney, R. E., Joormann, J., Eugene, F., Dennis, E. L., & Gotlib, I. H. (2010). Neural correlates of
ED

rumination in depression. Cognitive, Affective & Behavioral Neuroscience, 10(4), 470-478.

PT

doi:10.3758/CABN.10.4.470

Cowen, P. (2016). Altered states: psilocybin for treatment-resistant depression. The Lancet
CE

Psychiatry, 3(7), 592-593.

AC

Cryan, J. F., & O'Leary, O. F. (2010). Neuroscience. A glutamate pathway to faster-acting

antidepressants? Science (New York, N.Y.), 329(5994), 913-914. doi:10.1126/science.1194313

De Gregorio, D., Posa, L., Ochoa-Sanchez, R., McLaughlin, R., Maione, S., Comai, S., et al. (2016). The

hallucinogen d-lysergic diethylamide (LSD) decreases dopamine firing activity through 5-HT1A, D2

and TAAR1 receptors. Pharmacological Research, 113, 81-91.

 ACCEPTED MANUSCRIPT

Denny, B. T., Kober, H., Wager, T. D., & Ochsner, K. N. (2012). A meta-analysis of functional

neuroimaging studies of self- and other judgments reveals a spatial gradient for mentalizing in

medial prefrontal cortex. Journal of Cognitive Neuroscience, 24(8), 1742-1752.

doi:10.1162/jocn_a_00233

Deutschenbaur, L., Beck, J., Kiyhankhadiv, A., Muhlhauser, M., Borgwardt, S., Walter, M., et al. (2016).

T
Role of calcium, glutamate and NMDA in major depression and therapeutic application. Progress in

IP
Neuro-Psychopharmacology & Biological Psychiatry, 64, 325-333. doi:10.1016/j.pnpbp.2015.02.015

CR
Dichter, G. S., Gibbs, D., & Smoski, M. J. (2015). A systematic review of relations between resting-state

US
functional-MRI and treatment response in major depressive disorder. Journal of Affective

Disorders, 172, 8-17. doi:10.1016/j.jad.2014.09.028

AN
Doblin, R. (1991). Pahnke's "Good Friday Experiment": A long-term follow-up and methodological
M

critique. The Journal of Transpersonal Psychology, 23(1), 1-28.

ED

Doering-Silveira, E., Grob, C. S., de Rios, M. D., Lopez, E., Alonso, L. K., Tacla, C., et al. (2005). Report on

psychoactive drug use among adolescents using ayahuasca within a religious context. Journal of
PT

Psychoactive Drugs, 37(2), 141-144.

CE

dos Santos, R. G., Osório, F. L., Crippa, J. A. S., Riba, J., Zuardi, A. W., & Hallak, J. E. (2016).

Antidepressive, anxiolytic, and antiaddictive effects of ayahuasca, psilocybin and lysergic acid
AC

diethylamide (LSD): A systematic review of clinical trials published in the last 25 years. Therapeutic

Advances in Psychopharmacology, 6(3), 193-213.

Doucet, G., Naveau, M., Petit, L., Delcroix, N., Zago, L., Crivello, F., et al. (2011). Brain activity at rest: A

multiscale hierarchical functional organization. Journal of Neurophysiology, 105(6), 2753-2763.

doi:10.1152/jn.00895.2010
 ACCEPTED MANUSCRIPT

Drug Enforcement Agency. (2003). Pickard and Apperson sentenced on LSD charges. Retrieved from

https://www.dea.gov/pubs/states/newsrel/2003/sanfran112403.html

Drug Enforcement Agency. (2016). DEA statistics and facts. Retrieved from

https://www.dea.gov/resource-center/statistics.shtml

Duman, R. S., & Voleti, B. (2012). Signaling pathways underlying the pathophysiology and treatment of

T
IP
depression: Novel mechanisms for rapid-acting agents. Trends in Neurosciences, 35(1), 47-56.

CR
doi:10.1016/j.tins.2011.11.004

Duman, R. S., Li, N., Liu, R. J., Duric, V., & Aghajanian, G. (2012). Signaling pathways underlying the rapid

US
antidepressant actions of ketamine. Neuropharmacology, 62(1), 35-41.
AN
doi:10.1016/j.neuropharm.2011.08.044

Dutta, A., McKie, S., & Deakin, J. F. W. (2015) Ketamine and other potential glutamate
M

antidepressants. Psychiatry Research, 225(1), 1-13. doi:10.1016/j.psychres.2014.10.028

ED

Dyck, E. (2006). ‘Hitting highs at rock bottom’: LSD treatment for alcoholism, 1950 -1970. Social History
PT

of Medicine, 19(2), 313-329. doi:10.1093/shm/hkl039

El-Seedi, H., Smet, Peter A G M De, Beck, O., Possnert, G., & Bruhn, J. G. (2005). Prehistoric peyote use:
CE

Alkaloid analysis and radiocarbon dating of archaeological specimens of Lophophora from

AC

Texas. Journal of Ethnopharmacology, 101(1-3), 238-242. doi:10.1016/j.jep.2005.04.022

European Monitoring Centre for Drugs and Drug Addiction. (2016). European Drug Report 2016: Trends

and Developments. Publications Office of the European Union, Luxembourg

Fbregas, J. M., Gonzlez, D., Fondevila, S., Cutchet, M., Fernndez, X., Barbosa, P. C. R., & Bouso, J. C.

(2010). Assessment of addiction severity among ritual users of ayahuasca. Drug and Alcohol

Dependence, 111(3), 257-261. doi:10.1016/j.drugalcdep.2010.03.024

 ACCEPTED MANUSCRIPT

Finn, E. S., Shen, X., Scheinost, D., Rosenberg, M. D., Huang, J., Chun, M. M., & Constable, R. T. (2015).

Functional connectome fingerprinting: Identifying individuals using patterns of brain

connectivity. Nature Neuroscience, 18(11), 1664-1671. doi:10.1038/nn.4135

Froese, T., Guzmn, G., & Guzmn-Dvalos, L. (2016). On the origin of the genus psilocybe and its potential

ritual use in ancient Africa and Europe. Economic Botany, 70(2), 103-114.

T
IP
Garcia-Romeu, A., Griffiths, R. R., & Johnson, M. W. (2014). Psilocybin-occasioned mystical experiences

CR
in the treatment of tobacco addiction. Current Drug Abuse Reviews, 7(3), 157-164. doi:CDAR-EPUB-

64371 [pii]

US
Gasser, P., Holstein, D., Michel, Y., Doblin, R., Yazar-Klosinski, B., Passie, T., & Brenneisen, R. (2014).
AN
Safety and efficacy of lysergic acid diethylamide-assisted psychotherapy for anxiety associated with

life-threatening diseases. The Journal of Nervous and Mental Disease, 202(7), 513-520.
M

doi:10.1097/NMD.0000000000000113
ED

Gergen, M. K., Gergen, K. J., & Morse, S. J. (1972). Correlates of marijuana use among college

students. Journal of Applied Social Psychology, 2(1), 1-16. doi:10.1111/j.1559-1816.1972.tb01259.x

PT

Gilbert, S. J., Spengler, S., Simons, J. S., Frith, C. D., & Burgess, P. W. (2006). Differential functions of
CE

lateral and medial rostral prefrontal cortex (area 10) revealed by brain-behavior

associations. Cerebral Cortex (New York, N.Y.: 1991), 16(12), 1783-1789. doi:bhj113 [pii]
AC

Glenn, R. A., & Richards, L. G. (1974). Recent Surveys of Nonmedical Drug Use: A Compendium of

Abstracts.

Glennon, R.A., Young, R., & Rosecrans, J.A. (1983). Antagonism of the effects of the hallucinogen DOM

and the purported 5-HT agonist quipazine by 5-HT2 antagonists. European Journal of

Pharmacology, 91(2-3), 189–196.

 ACCEPTED MANUSCRIPT

Glennon, R.A., Titeler, M., & McKenney, J.D. (1984). Evidence for 5-HT2 involvement in the mechanism

of action of hallucinogenic agents. Life Sciences, 35(25), 2505–2511.

González-Maeso, J., Yuen, T., Ebersole, B. J., Wurmbach, E., Lira, A., Zhou, M., et al. (2003).

Transcriptome fingerprints distinguish hallucinogenic and nonhallucinogenic 5-hydroxytryptamine

2A receptor agonist effects in mouse somatosensory cortex. Journal of Neuroscience, 23(26), 8836-

T
8843.

IP
CR
Gouzoulis-Mayfrank, E., Heekeren, K., Thelen, B., Lindenblatt, H., Kovar, K. A., Sass, H., et al. (1998).

Effects of the hallucinogen psilocybin on habituation and prepulse inhibition of the startle reflex in

US
humans. Behavioural pharmacology, 9(7), 561-566.
AN
Gouzoulis-Mayfrank, E., Thelen, B., Habermeyer, E., Kunert, H. J., Kovar, K. A., Lindenblatt, H., et al.

(1999a). Psychopathological, neuroendocrine and autonomic effects of 3,4-

M

methylenedioxyethylamphetamine (MDE), psilocybin and d-methamphetamine in healthy

ED

volunteers. results of an experimental double-blind placebo-controlled

study. Psychopharmacology, 142(1), 41-50.

PT

Gouzoulis-Mayfrank, E., Schreckenberger, M., Sabri, O., Arning, C., Thelen, B., Spitzer, M., et al. (1999b).
CE

Neurometabolic effects of psilocybin, 3, 4-methylenedioxyethylamphetamine (MDE) and d-

methamphetamine in healthy volunteers: a double-blind, placebo-controlled PET study with [18F]

AC

FDG. Neuropsychopharmacology, 20(6), 565-581.

Gouzoulis-Mayfrank, E., Heekeren, K., Neukirch, A., Stoll, M., Stock, C., Obradovic, M., et al. (2005).

Psychological effects of (S)-ketamine and N, N-dimethyltryptamine (DMT): A double-blind, cross-

over study in healthy volunteers. Pharmacopsychiatry, 38(06), 301-311.

 ACCEPTED MANUSCRIPT

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. Psychopharmacology, 187(3), 92. doi:10.1007/s00213-006-0457-5

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

T
months later. Journal of Psychopharmacology (Oxford, England), 22(6), 621-632.

IP
doi:10.1177/0269881108094300

CR
Griffiths, R. R., Johnson, M. W., Richards, W. A., Richards, B. D., McCann, U., & Jesse, R. (2011).

US
Psilocybin occasioned mystical-type experiences: Immediate and persisting dose-related

effects. Psychopharmacology, 218(4), 649-665. doi:10.1007/s00213-011-2358-5

AN
Griffiths, R. R., Johnson, M. W., Carducci, M. A., Umbricht, A., Richards, W. A., Richards, B. D., et al.
M

(2016b). Psilocybin produces substantial and sustained decreases in depression and anxiety in
ED

patients with life-threatening cancer: A randomized double-blind trial. Journal of

Psychopharmacology (Oxford, England), 30(12), 1181-1197. doi:0269881116675513 [pii]

PT

Griffiths R.R., Johnson M.W., Richards W.R., Richards B.D., Jesse R., MacLean K.A., et al. (2018).
CE

Psilocybin-occasioned mystical-type experience in combination with meditation and other spiritual

practices produce enduring positive changes in trait measures of prosocial attitudes and
AC

behaviors. Journal of Psychopharmacology, 32 (1), 49-69.

Grinspoon, L. (1981). LSD reconsidered. The Sciences, 21(1), 20-23.

Grinspoon, L., & Bakalar, J. B. (1979). Psychedelic drugs reconsidered. New York: Basic Books.
 ACCEPTED MANUSCRIPT

Grob, C. S., Danforth, A. L., Chopra, G. S., Hagerty, M., McKay, C. R., Halberstadt, A. L., et al. (2011). Pilot

study of psilocybin treatment for anxiety in patients with advanced-stage cancer. Archives of

General Psychiatry, 68(1), 71-78. doi:10.1001/archgenpsychiatry.2010.116

Gu, H., Salmeron, B. J., Ross, T. J., Geng, X., Zhan, W., Stein, E. A., et al. (2010). Mesocorticolimbic circuits

are impaired in chronic cocaine users as demonstrated by resting-state functional

T
connectivity. NeuroImage, 53(2), 593-601. doi:10.1016/j.neuroimage.2010.06.066

IP
CR
Guerra-Doce, E. (2015). Psychoactive substances in prehistoric times: Examining the archaeological

evidence. Time & Mind: The Journal of Archaeology, Consciousness & Culture, 8(1), 91-112.

US
Halberstadt, A. L., & Geyer, M. A. (2011). Multiple receptors contribute to the behavioral effects of
AN
indoleamine hallucinogens. Neuropharmacology, 61(3), 364-381.

Halberstadt, A. L., & Geyer, M. A. (2013). Serotonergic hallucinogens as translational models relevant to
M

schizophrenia. International Journal of Neuropsychopharmacology, 16(10), 2165-2180.

ED

Halberstadt, A. L., Koedood, L., Powell, S. B., & Geyer, M. A. (2011). Differential contributions of
PT

serotonin receptors to the behavioral effects of indoleamine hallucinogens in mice. Journal of

Psychopharmacology, 25(11), 1548-1561.

CE

Halpern, J. H. (1996). The use of hallucinogens in the treatment of addiction. Addiction Research, 4(2),
AC

177-189. doi:10.3109/16066359609010756

Halpern, J. H., Sherwood, A. R., Hudson, J. I., Yurgelun-Todd, D., & Pope, H. G. J. (2005). Psychological

and cognitive effects of long-term peyote use among Native Americans. Biological Psychiatry, 58(8),

624-631. doi:10.1016/j.biopsych.2005.06.038
 ACCEPTED MANUSCRIPT

Halpern, J. H., Sherwood, A. R., Passie, T., Blackwell, K. C., & Ruttenber, A. J. (2008). Evidence of health

and safety in American members of a religion who use a hallucinogenic sacrament. Medical Science

Monitor: International Medical Journal of Experimental and Clinical Research, 14(8), 22.

Hasler, F., Grimberg, U., Benz, M. A., Huber, T., & Vollenweider, F. X. (2004). Acute psychological and

physiological effects of psilocybin in healthy humans: A double-blind, placebo-controlled dose-

T
effect study. Psychopharmacology, 172(2), 145-156. doi:10.1007/s00213-003-1640-6

IP
CR
Hasler, G., & Northoff, G. (2011). Discovering imaging endophenotypes for major depression. Molecular

Psychiatry, 16(6), 604-619.

US
Heekeren, K., Neukirch, A., Daumann, J., Stoll, M., Obradovic, M., Kovar, K. A., et al. (2007). Prepulse
AN
inhibition of the startle reflex and its attentional modulation in the human S-ketamine and N, N-

dimethyltryptamine (DMT) models of psychosis. Journal of Psychopharmacology, 21(3), 312-320.

M

Heffter, A. (1898). Beitrag zur chemischen und pharmakologischen Kenntnis der Cacteen. Archiv für
ED

Experimentelle Pathologie und Pharmakologie, 40(5-6), 385-429. doi:10.1007/BF01825267

PT

Hendricks, P. S., Johnson, M. W., & Griffiths, R. R. (2015a). Psilocybin, psychological distress, and

suicidality. Journal of Psychopharmacology, 29(9), 1041-1043. doi:10.1177/0269881115598338

CE

Hendricks, P. S., Clark, C. B., Johnson, M. W., Fontaine, K. R., & Cropsey, K. L. (2014). Hallucinogen use
AC

predicts reduced recidivism among substance-involved offenders under community corrections

supervision. Journal of Psychopharmacology, 28(1), 62-66. doi:10.1177/0269881113513851

Hendricks, P. S., Thorne, C. B., Clark, C. B., Coombs, D. W., & Johnson, M. W. (2015b). Classic psychedelic

use is associated with reduced psychological distress and suicidality in the united states adult

population. Journal of Psychopharmacology, 29(3), 280-288. doi:10.1177/0269881114565653

 ACCEPTED MANUSCRIPT

Hendricks, P. S., Crawford, M. S., Cropsey, K. L., Copes, H., Sweat, N. W., Walsh, Z., et al. (2018) The

relationships of classic psychedelic use with criminal behavior in the United States adult

population. Journal of Psychopharmacology, 32(1), 37-48. doi: 10.1177/0269881117735685

Hermle, L., Fünfgeld, M., Oepen, G., Botsch, H., Borchardt, D., Gouzoulis, E., et al. (1992). Mescaline-

induced psychopathological, neuropsychological, and neurometabolic effects in normal subjects:

T
Experimental psychosis as a tool for psychiatric research. Biological Psychiatry, 32(11), 976-991.

IP
doi:10.1016/0006-3223(92)90059-9

CR
Hoch, P. H. (1951). Experimentally produced psychoses. American Journal of Psychiatry, 107(8), 607-611.

US
Hoffer, A., Osmond, H., & Smythies, J. (1954). Schizophrenia: a new approach. II. Result of a year's
AN
research. Journal of Mental Science, 100(418), 29-45.

Hofmann, A., & Ott, J. (1980). LSD: My problem child. Translated by Jonathan Ott. New York: McGraw
M

Hill.
ED

Hofmann, A., Ott, J., & Feilding, A. (2013). LSD: My problem child and insights/outlooks. Oxford: Oxford
PT

University Press.

Hollister, L. E., Shelton, J., & Krieger, G. (1969). A controlled comparison of lysergic acid diethylamide
CE

(LSD) and dextroamphetamine in alcoholics. American Journal of Psychiatry, 125(10), 1352-1357.

AC

doi:10.1176/ajp.125.10.1352

Hood, J., Ralph W., Ghorbani, N., Watson, P. J., Ghramaleki, A. F., Bing, M. N., et al. (2001). Dimensions

of the mysticism scale: Confirming the three-factor structure in the United States and Iran. Journal

for the Scientific Study of Religion, 40(4), 691-705. doi:10.1111/0021-8294.00085

Hood, R. W. (1975). The construction and preliminary validation of a measure of reported mystical

experience. Journal for the Scientific Study of Religion, 14(1), 29-41. doi:10.2307/1384454
 ACCEPTED MANUSCRIPT

Hood R.W.J. (2009) Mysticism. In: R.W.J. Hood, P.C. Hill, & B. Spilka (Eds.) The Psychology of Religion

(4th ed.). New York: The Guilford Press.

Huxley, A. (1947). The perennial philosophy. London: Chatto & Windus.

Isbell, H. (1959). Comparison of the reactions induced by psilocybin and LSD-25 in

man. Psychopharmacologia, 1, 29-38.

T
IP
James, W. (1902). The varieties of religious experience. Jersey City: Start Publishing LLC.

CR
Jiang, G., Qiu, Y., Zhang, X., Han, L., Lv, X., Li, L., & Tian, J. (2011). Amplitude low-frequency oscillation

US
abnormalities in the heroin users: A resting state fMRI study. NeuroImage, 57(1), 149-154.

doi://doi.org/10.1016/j.neuroimage.2011.04.004
AN
Johansen, P., & Krebs, T. S. (2015). Psychedelics not linked to mental health problems or suicidal
M

behavior: A population study. Journal of Psychopharmacology, 29(3), 270-279.

doi:10.1177/0269881114568039
ED

Johnson M.W. (In Press). Psychiatry might need some psychedelic therapy. Introduction to issue: The
PT

renaissance in psychedelic research. International Review of Psychiatry.

CE

Johnson, M.W., & Griffiths, R.R. (2017). Potential therapeutic effects of psilocybin. Neurotherapeutics,

14 (3), 734-740.
AC

Johnson, M., Richards, W., & Griffiths, R. (2008). Human hallucinogen research: Guidelines for

safety. Journal of Psychopharmacology (Oxford, England), 22(6), 603-620.

doi:10.1177/0269881108093587
 ACCEPTED MANUSCRIPT

Johnson, M. W., Sewell, R. A., & Griffiths, R. R. (2012). Psilocybin dose-dependently causes delayed,

transient headaches in healthy volunteers. Drug and Alcohol Dependence, 123(1-3), 132-140.

doi:10.1016/j.drugalcdep.2011.10.029

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. Journal of Psychopharmacology (Oxford,

T
England), 28(11), 983-992. doi:10.1177/0269881114548296

IP
CR
Johnson, M. W., Garcia-Romeu, A., & Griffiths, R. R. (2017a). Long-term follow-up of psilocybin-

facilitated smoking cessation. The American Journal of Drug and Alcohol Abuse, 43(1), 55-60.

US
doi:10.3109/00952990.2016.1170135 AN
Johnson, M. W., Garcia-Romeu, A., Johnson, P. S., & Griffiths, R. R. (2017b). An online survey of tobacco

smoking cessation associated with naturalistic psychedelic use. Journal of Psychopharmacology

M

(Oxford, England), 31(7), 841-850. doi:10.1177/0269881116684335

ED

Johnson, M. W., Griffiths, R. R., Hendricks, P. S., & Henningfield, J. E. (2018). The abuse potential of

medical psilocybin according to the 8 factors of the Controlled Substances

PT

Act. Neuropharmacology. doi: 10.1016/j.neuropharm.2018.05.012. [Epub ahead of print]

CE

Johnston, L. (1973). Drugs and American Youth. A report from the Youth in Transition Project for the

Institute of Social Research at University of Michigan.

AC

Jones, R. H. (2016). Philosophy of mysticism: Raids on the ineffable. Herndon, VA: SUNY Press.

Kast, E. (1967). Attenuation of anticipation: A therapeutic use of lysergic acid diethylamide. Psychiatric

Quarterly, 41(4), 646-657. doi:10.1007/BF01575629

Kast, E. C., & Collins, V. J. (1964a). Study of lysergic acid diethylamide as an analgesic agent. Anesthesia

and Analgesia, 43, 285-291.

 ACCEPTED MANUSCRIPT

Ketchum, J. S. (2006). Chemical warfare: Secrets almost forgotten. Santa Rosa, CA: ChemBooks.

Klimesch, W. (2012). Alpha-band oscillations, attention, and controlled access to stored

information. Trends in Cognitive Sciences, 16(12), 606-617. doi:10.1016/j.tics.2012.10.007

Kometer, M., Schmidt, A., Jancke, L., & Vollenweider, F. X. (2013). Activation of serotonin 2A receptors

underlies the psilocybin-induced effects on alpha oscillations, N170 visual-evoked potentials, and

T
IP
visual hallucinations. The Journal of Neuroscience: The Official Journal of the Society for

CR
Neuroscience, 33(25), 10544-10551. doi:10.1523/JNEUROSCI.3007-12.2013

Kometer, M., Pokorny, T., Seifritz, E., & Volleinweider, F. X. (2015). Psilocybin-induced spiritual

US
experiences and insightfulness are associated with synchronization of neuronal
AN
oscillations. Psychopharmacology, 232(19), 3663-3676. doi:10.1007/s00213-015-4026-7

Kometer, M., Schmidt, A., Bachmann, R., Studerus, E., Seifritz, E., & Vollenweider, F. X. (2012). Psilocybin
M

biases facial recognition, goal-directed behavior, and mood state toward positive relative to
ED

negative emotions through different serotonergic subreceptors. Biological Psychiatry, 72(11),

898-906.
PT

Krebs, T. S., & Johansen, P. O. (2012). Lysergic acid diethylamide (LSD) for alcoholism: Meta-analysis of
CE

randomized controlled trials. Journal of Psychopharmacology (Oxford, England), 26(7), 994-1002.

doi:10.1177/0269881112439253
AC

Krebs, T. S., & Johansen, P. (2013). Psychedelics and mental health: A population study. PLoS

ONE, 8(e63972) doi:10.1371/journal.pone.0063972

Krystal, J. H., Sanacora, G., & Duman, R. S. (2013). Rapid-acting glutamatergic antidepressants: The path

to ketamine and beyond. Biological Psychiatry, 73(12), 1133-1141.

doi:10.1016/j.biopsych.2013.03.026
 ACCEPTED MANUSCRIPT

Kubit, B., & Jack, A. I. (2013). Rethinking the role of the rTPJ in attention and social cognition in light of

the opposing domains hypothesis: Findings from an ALE-based meta-analysis and resting-state

functional connectivity. Frontiers in Human Neuroscience, 7, 323. doi:10.3389/fnhum.2013.00323

Kucyi, A., Moayedi, M., Weissman-Fogel, I., Goldberg, M. B., Freeman, B. V., Tenenbaum, H. C., et al.

(2014). Enhanced medial prefrontal-default mode network functional connectivity in chronic pain

T
and its association with pain rumination. The Journal of Neuroscience: The Official Journal of the

IP
Society for Neuroscience, 34(11), 3969-3975. doi:10.1523/JNEUROSCI.5055-13.2014

CR
Kurland, A. A. (1985). LSD in the supportive care of the terminally ill cancer patient. Journal of

US
Psychoactive Drugs, 17(4), 279-290. doi:10.1080/02791072.1985.10524332
AN
Kurland, A. A., Grof, S., Pahnke, W. N., & Goodman, L. E. (1973). Psychedelic drug assisted

psychotherapy. In I. K. Goldberg, S. Malitz & A. H. Kutscher (Eds.), Patients with terminal cancer
M

psychotheramacological agents for the terminally ill and bereaved (pp. 86-133). New York, NY:
ED

Columbia University Press.

Kurland, A. A., Pahnke, W. N., Unger, S., Savage, C., & Goodman, L. E. (1969). Psychedelic psychotherapy
PT

(LSD) in the treatment of the patient with a malignancy. In A. Cerletti, & F. Bové (Eds.), The present
CE

status of psychotropic drugs: Pharmacological and clinical aspects (pp. 432-434). Amsterdam:

Excerpts Medica.
AC

Kurland, A., Savage, C., Pahnke, W. N., Grof, S., & Olsson, J. E. (1971). LSD in the treatment of

alcoholics. Pharmacopsychiatry, 4(2), 83-94. doi:10.1055/s-0028-1094301

Kyzar, E. J., Nichols, C. D., Gainetdinov, R. R., Nichols, D. E., & Kalueff, A. V. (2017). Psychedelic drugs in

biomedicine. Trends in Pharmacological Sciences, 38(11), 992-1005.

 ACCEPTED MANUSCRIPT

Lawn, W., Barratt, M., Williams, M., Horne, A., & Winstock, A. (2014). The NBOMe hallucinogenic drug

series: Patterns of use, characteristics of users and self-reported effects in a large international

sample. Journal of Psychopharmacology, 28(8), 780-788. doi:10.1177/0269881114523866

Leary, T. (1969). The effects of consciousness-expanding drugs on prisoner rehabilitation. Psychedelic

Review, 10, 29-45.

T
IP
Lebedev, A. V., Kaelen, M., Lovden, M., Nilsson, J., Feilding, A., Nutt, D. J., et al. (2016). LSD-induced

CR
entropic brain activity predicts subsequent personality change. Human Brain Mapping, 37(9), 3203-

3213. doi:10.1002/hbm.23234

US
Lebedev, A. V., Lovden, M., Rosenthal, G., Feilding, A., Nutt, D. J., & Carhart-Harris, R. L. (2015). Finding
AN
the self by losing the self: Neural correlates of ego-dissolution under psilocybin. Human Brain

Mapping, 36(8), 3137-3153. doi:10.1002/hbm.22833

M

Lee, M. A., & Slain, B. (1992). Acid dreams: The complete social history of LSD: The CIA, the sixties, and
ED

beyond (revised ed.). New York: Grove Press.

PT

Leech, R., & Sharp, D. J. (2014). The role of the posterior cingulate cortex in cognition and disease. Brain:

A Journal of Neurology, 137(Pt 1), 12-32. doi:10.1093/brain/awt162

CE

Leibenluft, E., & Pine, D. S. (2013). Resting state functional connectivity and depression: In search of a
AC

bottom line. Biological Psychiatry, 74(12), 868-869. doi:10.1016/j.biopsych.2013.10.001

Lerman, C., Gu, H., Loughead, J., Ruparel, K., Yang, Y., & Stein, E. A. (2014). Large-scale brain network

coupling predicts acute nicotine abstinence effects on craving and cognitive function. JAMA

Psychiatry, 71(5), 523-530. doi:10.1001/jamapsychiatry.2013.4091

Levitt, S. H. (2011). New considerations regarding the identity of vedic sóma as the mushroom fly-

agaric. Studia Orientalia, 111, 105-118.

 ACCEPTED MANUSCRIPT

Lewis, C. R., Preller, K. H., Kraehenmann, R., Michels, L., Staempfli, P., & Vollenweider, F. X. (2017). Two

dose investigation of the 5-HT-agonist psilocybin on relative and global cerebral blood

flow. NeuroImage, 159, 70-78. doi:S1053-8119(17)30588-8 [pii]

Liechti, M. E., Dolder, P. C., & Schmid, Y. (2017). Alterations of consciousness and mystical-type

experiences after acute LSD in humans. Psychopharmacology, 234(9-10), 1499-1510.

T
doi:10.1007/s00213-016-4453-0

IP
CR
Linstock, A., Barrat, M., Ferris, J., & Maier, L. (2017). Global drug survey key findings 2017.

Lozano, A. M., Giacobbe, P., Hamani, C., Rizvi, S. J., Kennedy, S. H., Kolivakis, T. T., & Mayberg, H. S.

US
(2012). A multicenter pilot study of subcallosal cingulate area deep brain stimulation for treatment-
AN
resistant depression. Journal of Neurosurgery, 116(2), 315-322. doi:10.3171/2011.10.JNS102122

Lu, H., Zou, Q., Chefer, S., Ross, T. J., Vaupel, D. B., Guillem, K., & Stein, E. A. (2014). Abstinence from
M

cocaine and sucrose self-administration reveals altered mesocorticolimbic circuit connectivity by

ED

resting state MRI. Brain Connectivity, 4(7), 499-510. doi:10.1089/brain.2014.0264

PT

Ludwig, A., Levine, J., Stark, L., & Lazar, R. (1969). A clinical study of LSD treatment in

alcoholism. American Journal of Psychiatry, 126(1), 59-69. doi:10.1176/ajp.126.1.59

CE

MacLean, K. A., Johnson, M. W., & Griffiths, R. R. (2011). Mystical experiences occasioned by the
AC

hallucinogen psilocybin lead to increases in the personality domain of openness. Journal of

Psychopharmacology (Oxford, England), 25(11), 1453-1461. doi:10.1177/0269881111420188

Maclean, K. A., Leoutsakos, J. M., Johnson, M. W., & Griffiths, R. R. (2012). Factor analysis of the mystical

experience questionnaire: A study of experiences occasioned by the hallucinogen

psilocybin. Journal for the Scientific Study of Religion, 51(4), 721-737. doi:10.1111/j.1468-

5906.2012.01685.x
 ACCEPTED MANUSCRIPT

Mahapatra, A., & Gupta, R. (2017). Role of psilocybin in the treatment of depression. Therapeutic

Advances in Psychopharmacology, 7(1), 54-56.

Majic, T., Schmidt, T. T., & Gallinat, J. (2015). Peak experiences and the afterglow phenomenon: When

and how do therapeutic effects of hallucinogens depend on psychedelic experiences? Journal of

Psychopharmacology (Oxford, England), 29(3), 241-253. doi:10.1177/0269881114568040

T
IP
Mangini, M. (1998). Treatment of alcoholism using psychedelic drugs: A review of the program of

CR
research. Journal of Psychoactive Drugs, 30(4), 381-418. doi:10.1080/02791072.1998.10399714

Maslow, A. H. (1968). Toward a psychology of being. New York: Van Nostrand.

US
Mayberg, H. S., Lozano, A. M., Voon, V., McNeely, H. E., Seminowicz, D., Hamani, C., & Kennedy, S. H.
AN
(2005). Deep brain stimulation for treatment-resistant depression. Neuron, 45(5), 651-660.

doi:10.1016/j.neuron.2005.02.014
M

McGlothlin, W. H., & Arnold, D. O. (1971). LSD revisited. A ten-year follow-up of medical LSD
ED

use. Archives of General Psychiatry, 24(1), 35-49.

PT

McKenna, T. (1993). Food of the gods: The search for the original tree of knowledge, A radical history of

plants, drugs, and human evolution. New York: Bantam.

CE

McCorvy, J. D., Olsen, R. H., & Roth, B. L. (2016). Psilocybin for depression and anxiety associated with
AC

life-threatening illnesses. Journal of Psychopharmacology, 30(12), 1209-1210.

Miech, R. A., Johnston, L. D., O'Malley, P. M., Bachman, J. G., Schulenberg, J. E., & Patrick, M. E. (2017).

Monitoring the future study national survey results on drug use, 1975-2016: Volume 1, secondary

school students. Ann Arbor: Institute for Social Research, The University of Michigan.
 ACCEPTED MANUSCRIPT

Miller, W. R. (2004). The phenomenon of quantum change. Journal of Clinical Psychology, 60(5), 453-

460. doi:10.1002/jclp.20000

Miranda, C. T., Labigalini, E.,Jr, & Tacla, C. (1995). Alternative religion and outcome of alcohol

dependence in brazil. Addiction (Abingdon, England), 90(6), 847.

Moreno, F. A., Wiegand, C. B., Taitano, E. K., & Delgado, P. L. (2006). Safety, tolerability, and efficacy of

T
IP
psilocybin in 9 patients with obsessive-compulsive disorder. The Journal of Clinical

CR
Psychiatry, 67(11), 1735-1740.

Morris, H., & Wallach, J. (2014). From PCP to MXE: A comprehensive review of the non-medical use of

US
dissociative drugs. Drug Testing and Analysis, 6(7-8), 614-632. doi:10.1002/dta.1620
AN
Murray, R. M., Paparelli, A., Morrison, P. D., Marconi, A., & Di Forti, M. (2013). What can we learn about

schizophrenia from studying the human model, drug‐induced psychosis? American Journal of
M

Medical Genetics Part B: Neuropsychiatric Genetics, 162(7), 661-670.

ED

Muthukumaraswamy, S. D., Carhart-Harris, R. L., Moran, R. J., Brookes, M. J., Williams, T. M., Errtizoe,
PT

D., & Nutt, D. J. (2013). Broadband cortical desynchronization underlies the human psychedelic

state. The Journal of Neuroscience: The Official Journal of the Society for Neuroscience, 33(38),
CE

15171-15183. doi:10.1523/JNEUROSCI.2063-13.2013
AC

Nichols, D. E. (2016). Psychedelics. Pharmacological Reviews, 68(2), 264-355. doi:10.1124/pr.115.011478

Nichols, D. E., Lloyd, D. H., Hoffman, A. J., Nichols, M. B., & Yim, G. K. (1982). Effects of certain

hallucinogenic amphetamine analogues on the release of [3H]serotonin from rat brain

synaptosomes. Journal of Medicinal Chemistry, 25(5), 530-535.

Nutt, D. J., King, L. A., & Nichols, D. E. (2013). Effects of schedule I drug laws on neuroscience research

and treatment innovation. Nature Reviews. Neuroscience, 14(8), 577-585. doi:10.1038/nrn3530

 ACCEPTED MANUSCRIPT

Osmond, H. (1957). A review of the clinical effects of psychotomimetic agents. Annals of the New York

Academy of Sciences, 66(3), 418-434. doi:10.1111/j.1749-6632.1957.tb40738.x

Osório, F. D. L., Sanches, R. F., Macedo, L. R., Dos Santos, R. G., Maia-de-Oliveira, J. P., Wichert-Ana, L., et

al. (2015). Antidepressant effects of a single dose of ayahuasca in patients with recurrent

depression: a preliminary report. Revista Brasileira de Psiquiatria, 37(1), 13-20.

T
IP
Pahnke, W.N. (1963). Drugs and mysticism: An analysis of the relationship between psychedelic drugs

CR
and the mystical consciousness. Cambridge, MA: Harvard University Press.

Pahnke, W. (1967a). The contribution of the psychology of religion to the therapeutic use of the

US
psychedelic substances. In: H.A. Abramson HA (Ed.) The use of LSD in psychotherapy and
AN
alcoholism. (pp. 629-649). Indianapolis: The Bobbs-Merrill Company, Inc.,

Pahnke, W. (1967b). LSD and religious experience. In: R.C. DeBold, R.C. Leaf (Eds.) LSD man & society.
M

(pp. 60-85). Middletown: Wesleyan University Press,

ED

Pahnke, W. N. (1969). Psychedelic drugs and mystical experience. International Psychiatry Clinics, 5(4),
PT

149-162.

Pahnke, W. N., & Richards, W. A. (1966). Implications of LSD and experimental mysticism. Journal of
CE

Religion and Health, 5(3), 175-208. doi:10.1007/BF01532646

AC

Pahnke, W. N., Kurland, A. A., Goodman, L. E., & Richards, W. A. (1969). LSD-assisted psychotherapy with

terminal cancer patients. Current Psychiatric Therapies, 9, 144-152.

Palhano-Fontes, F., Andrade, K. C., Tofoli, L. F., Santos, A. C., Crippa, J. A., Hallak, J. E., et al. (2015). The

psychedelic state induced by ayahuasca modulates the activity and connectivity of the default

mode network. PloS One, 10(2), e0118143. doi:10.1371/journal.pone.0118143

 ACCEPTED MANUSCRIPT

Palhano-Fontes, F., Barreto, D., Onias, H., Andrade, K. C., Novaes, M. M., Pessoa, J. A., et al. (2018).

Rapid antidepressant effects of the psychedelic ayahuasca in treatment-resistant depression: a

randomized placebo-controlled trial. Psychological Medicine, 1-9. [Epub ahead of print].

Passie, T., Seifert, J., Schneider, U., & Emrich, H. M. (2002). The pharmacology of psilocybin. Addiction

Biology, 7(4), 357-364. doi:10.1080/1355621021000005937

T
IP
Patra, S. (2016). Return of the psychedelics: Psilocybin for treatment resistant depression. Asian Journal

CR
of Psychiatry, 24, 51-52.

Petri, G., Expert, P., Turkheimer, F., Carhart-Harris, R., Nutt, D., Hellyer, P. J., & Vaccarino, F. (2014).

US
Homological scaffolds of brain functional networks. Journal of the Royal Society, Interface, 11(101),
AN
20140873.

Pisano, V. D., Putnam, N. P., Kramer, H. M., Franciotti, K. J., Halpern, J. H., & Holden, S. C. (2017). The
M

association of psychedelic use and opioid use disorders among illicit users in the United
ED

States. Journal of Psychopharmacology, 31(5), 606-613. doi:10.1177/0269881117691453

PT

Power, J. D., Cohen, A. L., Nelson, S. M., Wig, G. S., Barnes, K. A., Church, J. A., & Petersen, S. E. (2011).

Functional network organization of the human brain. Neuron, 72(4), 665-678.

CE

doi:10.1016/j.neuron.2011.09.006
AC

Preller, K. H., & Vollenweider, F. X. (2016). Phenomenology, structure, and dynamic of psychedelic

states. Current Topics in Behavioral Neurosciences, doi:10.1007/7854_2016_459

Preller, K. H., Pokorny, T., Hock, A., Kraehenmann, R., Stampfli, P., Seifritz, E., & Vollenweider, F. X.

(2016). Effects of serotonin 2A/1A receptor stimulation on social exclusion processing. Proceedings

of the National Academy of Sciences of the United States of America, 113(18), 5119-5124.

doi:10.1073/pnas.1524187113
 ACCEPTED MANUSCRIPT

Price, J. L., & Drevets, W. C. (2012). Neural circuits underlying the pathophysiology of mood

disorders. Trends in Cognitive Sciences, 16(1), 61-71. doi:10.1016/j.tics.2011.12.011

Prue, B. (2014). Prevalence of reported peyote use 1985-2010 effects of the American Indian Religious

Freedom Act of 1994. American Journal on Addictions, 23(2), 156-161.

Quednow, B. B., Kometer, M., Geyer, M. A., & Vollenweider, F. X. (2012). Psilocybin-induced deficits in

T
IP
automatic and controlled inhibition are attenuated by ketanserin in healthy human

CR
volunteers. Neuropsychopharmacology, 37(3), 630.

Ramirez-Mahaluf, J. P., Roxin, A., Mayberg, H. S., & Compte, A. (2017). A computational model of major

US
depression: The role of glutamate dysfunction on cingulo-frontal network dynamics. Cerebral
AN
Cortex (New York, N.Y.: 1991), 27(1), 660-679. doi:10.1093/cercor/bhv249

Response Analysis Corporation. (1973). Drug experience, attitudes and related behavior among
M

adolescents and adults: Detailed tabulations, part 2c. experience data. A nationwide study for the
ED

national commission on marihuana and drug abuse.

PT

Riba, J., Anderer, P., Jane, F., Saletu, B., & Barbanoj, M. J. (2004). Effects of the South American

psychoactive beverage ayahuasca on regional brain electrical activity in humans: A functional

CE

neuroimaging study using low-resolution electromagnetic tomography. Neuropsychobiology, 50(1),

89-101. doi:10.1159/000077946
AC

Riba, J., Anderer, P., Morte, A., Urbano, G., Jane, F., Saletu, B., & Barbanoj, M. J. (2002). Topographic

pharmaco-EEG mapping of the effects of the South American psychoactive beverage ayahuasca in

healthy volunteers. British Journal of Clinical Pharmacology, 53(6), 613-628. doi:1609 [pii]

Richards, W. (1979). Psychedelic drug-assisted psychotherapy with persons suffering from terminal

cancer. Journal of Altered States of Consciousness, 5(4), 309-319.

 ACCEPTED MANUSCRIPT

Richards, W., Grof, S., Goodman, L., & Kurland, A. (1972). LSD-assisted psychotherapy and the human

encounter with death. The Journal of Transpersonal Psychology, 4(2), 121.

Richards, W. A., Rhead, J. C., Dileo, F. B., Yensen, R., & Kurland, A. A. (1977). The peak experience

variable in DPT-assisted psychotherapy with cancer patients. Journal of Psychedelic Drugs, 9(1), 1-

10. doi:10.1080/02791072.1977.10472020

T
IP
Richards, W. A., Rhead, J. C., Grof, S., Goodman, L. E., Leo, F. D., & Rush, L. (1979). DPT as an adjunct in

CR
brief psychotherapy with cancer patients. OMEGA--Journal of Death and Dying, 10(1), 9-26.

doi:10.2190/NGUB-V4RM-T7DC-XTH3Roberts, T. B. (Ed.) (2001). Psychoactive sacramental: essays

US
on etheogens and religion. San Francisco: Council on Spiritual Practices.
AN
Roseman, L., Demetriou, L., Wall, M.B., Nutt, D.J., & Carhart-Harris, R.L. (2017). Increased amygdala

responses to emotional faces after psilocybin for treatment-resistant depression.

M

Neuropharmacology. doi: 10.1016/j.neuropharm.2017.12.041. [Epub ahead of print].

ED

Ross, S., Bossis, A., Guss, J., Agin-Liebes, G., Malone, T., Cohen, B., & Schmidt, B. L. (2016). Rapid and

sustained symptom reduction following psilocybin treatment for anxiety and depression in patients
PT

with life-threatening cancer: A randomized controlled trial. Journal of Psychopharmacology

CE

(Oxford, England), 30(12), 1165-1180. doi:0269881116675512 [pii]

Rossi, P., Groves, W., & Grafstein, D. (1972). Life style and campus communities: A report of a survey of
AC

American colleges and universities (1969-70).

Salvadore, G., van der Veen, J W, Zhang, Y., Marenco, S., Machado-Vieira, R., Baumann, J., & Zarate, C. A.

(2012). An investigation of amino-acid neurotransmitters as potential predictors of clinical

improvement to ketamine in depression. The International Journal of

Neuropsychopharmacology, 15(8), 1063-1072. doi:10.1017/S1461145711001593

 ACCEPTED MANUSCRIPT

Sanacora, G., Zarate, C. A., Krystal, J. H., & Manji, H. K. (2008). Targeting the glutamatergic system to

develop novel, improved therapeutics for mood disorders. Nature Reviews Drug Discovery, 7(5),

426-437.

Sanches, R. F., de Lima Osório, F., Dos Santos, R. G., Macedo, L. R., Maia-de-Oliveira, J. P., Wichert-Ana,

L., et al. (2016). Antidepressant effects of a single dose of ayahuasca in patients with recurrent

T
depression: A SPECT study. Journal of Clinical Psychopharmacology, 36(1), 77-81.

IP
CR
Savage, C., & McCabe, O. L. (1973). Residential psychedelic (LSD) therapy for the narcotic addict: A

controlled study. Archives of General Psychiatry, 28(6), 808-814.

US
doi:10.1001/archpsyc.1973.01750360040005 AN
Schartner, M., Carhart-Harris, R., Barrett, A., Seth, A., & Muthukumaraswamy, S. (2017). Increased

spontaneous MEG signal diversity for psychoactive doses of ketamine, LSD and psilocybin. Scientific
M

Reports, 7, 46421. doi:10.1038/srep46421

ED

Schultes, R. E. (1969). Hallucinogens of plant origin. Science (New York, N.Y.), 163(3864), 245-254.
PT

Schultes, R., Hofmann, A., & Rätsch, C. (2001). Plants of the gods: Their sacred, healing, and

hallucinogenic powers (2nd ed., Rev. and expanded ed.). Rochester: Healing Arts Press.
CE

Seminowicz, D. A., Mayberg, H. S., McIntosh, A. R., Goldapple, K., Kennedy, S., Segal, Z., & Rafi-Tari, S.
AC

(2004). Limbic-frontal circuitry in major depression: A path modeling

metanalysis. NeuroImage, 22(1), 409-418. doi:10.1016/j.neuroimage.2004.01.015

Sewell, R. A., Halpern, J. H., & Pope, H. G. (2006). Response of cluster headache to psilocybin and

LSD. Neurology, 66(12), 1920-1922. doi:66/12/1920 [pii]

 ACCEPTED MANUSCRIPT

Shirer, W. R., Ryali, S., Rykhlevskaia, E., Menon, V., & Greicius, M. D. (2012). Decoding subject-driven

cognitive states with whole-brain connectivity patterns. Cerebral Cortex (New York, N.Y.:

1991), 22(1), 158-165. doi:10.1093/cercor/bhr099

Shulgin, A., & Shulgin, A. (1991). PiHKAL. Berkeley: Transform Press.

Skolnick, P., Popik, P., & Trullas, R. (2009). Glutamate-based antidepressants: 20 years on. Trends in

T
IP
Pharmacological Sciences, 30(11), 563-569. doi:10.1016/j.tips.2009.09.002

CR
Smith, H. (2000). Cleansing the doors of perception: The religious significance of entheogenic plants and

chemicals. New York: Tarcher/Putnam.

US
Smith, S. M., Fox, P. T., Miller, K. L., Glahn, D. C., Fox, P. M., Mackay, C. E., & Beckmann, C. F. (2009).
AN
Correspondence of the brain's functional architecture during activation and rest. Proceedings of the

National Academy of Sciences of the United States of America, 106(31), 13040-13045.

M

doi:10.1073/pnas.0905267106
ED

Speth, J., Speth, C., Kaelen, M., Schloerscheidt, A. M., Feilding, A., Nutt, D. J., & Carhart-Harris, R. L.
PT

(2016). Decreased mental time travel to the past correlates with default-mode network

disintegration under lysergic acid diethylamide. Journal of Psychopharmacology (Oxford,

CE

England), 30(4), 344-353. doi:10.1177/0269881116628430

AC

Spitzer, M., Thimm, M., Hermle, L., Holzmann, P., Kovar, K. A., Heimann, H., & Schneider, F. (1996).

Increased activation of indirect semantic associations under psilocybin. Biological

Psychiatry, 39(12), 1055-1057. doi:0006-3223(95)00418-1 [pii]

Sporns, O. (2011). The human connectome: A complex network. Annals of the New York Academy of

Sciences, 1224, 109-125. doi:10.1111/j.1749-6632.2010.05888.x

Stace, W. T. (1960a). The teachings of the mystics. New York: New American Library.
 ACCEPTED MANUSCRIPT

Stace, W. T. (1960b). Mysticism and philosophy. Philadelphia: Lippincott.

Stevens, J. (1987). Storming heaven: LSD and the American dream. New York: The Atlantic Monthly

Press.

Strassman, R. J., & Qualls, C. R. (1994). Dose-response study of N,N-dimethyltryptamine in humans. I.

neuroendocrine, autonomic, and cardiovascular effects. Archives of General Psychiatry, 51(2), 85-

T
IP
97.

CR
Sutherland, M. T., McHugh, M. J., Pariyadath, V., & Stein, E. A. (2012). Resting state functional

connectivity in addiction: Lessons learned and a road ahead. NeuroImage, 62(4), 2281-2295.

US
doi:10.1016/j.neuroimage.2012.01.117
AN
Svoboda, E., McKinnon, M. C., & Levine, B. (2006). The functional neuroanatomy of autobiographical

memory: A meta-analysis. Neuropsychologia, 44(12), 2189-2208. doi:S0028-3932(06)00209-0 [pii]

M

Tagliazucchi, E., Carhart-Harris, R., Leech, R., Nutt, D., & Chialvo, D. R. (2014). Enhanced repertoire of
ED

brain dynamical states during the psychedelic experience. Human Brain Mapping, 35(11), 5442-
PT

5456. doi:10.1002/hbm.22562

Tagliazucchi, E., Roseman, L., Kaelen, M., Orban, C., Muthukumaraswamy, S. D., Murphy, K., et al.
CE

(2016). Increased global functional connectivity correlates with LSD-induced ego

AC

dissolution. Current Biology: CB, 26(8), 1043-1050. doi:10.1016/j.cub.2016.02.010

Tenenbaum, B. (1961). Group therapy with LSD-25. (A preliminary report). Diseases of the Nervous

System, 22, 459-462.

Tomsovic, M., & Edwards, R.V. (1970). Lysergide treatment of schizophrenic and nonschizophrenic

alcoholics: A controlled evaluation. Quarterly Journal of Studies on Alcohol, 31(4), 932-949.

 ACCEPTED MANUSCRIPT

United States Department of Health and Human Services, Substance Abuse and Mental Health Services

Administration, & Center for Behavioral Health Statistics and Quality (n.d.). National Survey on

Drug Use and Health, 1991. Ann Arbor: Inter-university Consortium for Political and Social

Research.

United States Department of Health and Human Services, Substance Abuse and Mental Health Services

T
Administration, & Center for Behavioral Health Statistics and Quality. (1991a). National Survey on

IP
Drug Use and Health, 1988. Ann Arbor: Inter-university Consortium for Political and Social

CR
Research.

US
United States Department of Health and Human Services, Substance Abuse and Mental Health Services

Administration, & Center for Behavioral Health Statistics and Quality. (1991b). National Survey on
AN
Drug Use and Health, 1990. Ann Arbor: Inter-university Consortium for Political and Social
M

Research.
ED

United States Department of Health and Human Services, Substance Abuse and Mental Health Services

Administration, & Center for Behavioral Health Statistics and Quality. (1994a). National Survey on
PT

Drug Use and Health, 1985. Ann Arbor: Inter-university Consortium for Political and Social

Research.
CE

United States Department of Health and Human Services, Substance Abuse and Mental Health Services
AC

Administration, & Center for Behavioral Health Statistics and Quality. (1994b). National Survey on

Drug Use and Health, 1992. Ann Arbor: Inter-university Consortium for Political and Social

Research.

United States Department of Health and Human Services, Substance Abuse and Mental Health Services

Administration, & Center for Behavioral Health Statistics and Quality. (1995). National Survey on
 ACCEPTED MANUSCRIPT

Drug Use and Health, 1993. Ann Arbor: Inter-university Consortium for Political and Social

Research.

United States Department of Health and Human Services, Substance Abuse and Mental Health Services

Administration, & Center for Behavioral Health Statistics and Quality. (1996). National Survey on

Drug Use and Health, 1994. Ann Arbor: Inter-university Consortium for Political and Social

T
Research.

IP
CR
United States Department of Health and Human Services, Substance Abuse and Mental Health Services

Administration, & Center for Behavioral Health Statistics and Quality. (1997). National Survey on

US
Drug Use and Health, 1995. Ann Arbor: Inter-university Consortium for Political and Social

Research.
AN
United States Department of Health and Human Services, Substance Abuse and Mental Health Services
M

Administration, & Center for Behavioral Health Statistics and Quality. (1998). National Survey on
ED

Drug Use and Health, 1996. Ann Arbor: Inter-university Consortium for Political and Social

Research.
PT

United States Department of Health and Human Services, Substance Abuse and Mental Health Services
CE

Administration, & Center for Behavioral Health Statistics and Quality. (1999). National Survey on

Drug Use and Health, 1997. Ann Arbor.: Inter-university Consortium for Political and Social
AC

Research.

United States Department of Health and Human Services, Substance Abuse and Mental Health Services

Administration, & Center for Behavioral Health Statistics and Quality. (2000). National Survey on

Drug Use and Health, 1998. Ann Arbor: Inter-university Consortium for Political and Social

Research.
 ACCEPTED MANUSCRIPT

United States Department of Health and Human Services, Substance Abuse and Mental Health Services

Administration, & Center for Behavioral Health Statistics and Quality. (2006a). National Survey on

Drug Use and Health, 1999. Ann Arbor: Inter-university Consortium for Political and Social

Research.

United States Department of Health and Human Services, Substance Abuse and Mental Health Services

T
Administration, & Center for Behavioral Health Statistics and Quality. (2006b). Survey on Drug Use

IP
and Health, 2000. Ann Arbor: Inter-university Consortium for Political and Social Research.

CR
United States Department of Health and Human Services, Substance Abuse and Mental Health Services

US
Administration, & Center for Behavioral Health Statistics and Quality. (2006c). National Survey on

Drug Use and Health, 2001. Ann Arbor: Inter-university Consortium for Political and Social
AN
Research.
M

United States Department of Health and Human Services, Substance Abuse and Mental Health Services
ED

Administration, & Center for Behavioral Health Statistics and Quality. (2012a). Drug Abuse Warning

Network, 2004-2011. Ann Arbor: Inter-university Consortium for Political and Social Research.
PT

United States Department of Health and Human Services, Substance Abuse and Mental Health Services
CE

Administration, & Center for Behavioral Health Statistics and Quality. (2012b). Drug abuse warning

network methodology report, 2010 update. Rockville, MD: Substance Abuse and Mental Health
AC

Services Administration.

United States Department of Health and Human Services, Substance Abuse and Mental Health Services

Administration, & Center for Behavioral Health Statistics and Quality. (2012c). National Survey on

Drug Use and Health, 2002. Ann Arbor: Inter-university Consortium for Political and Social

Research.
 ACCEPTED MANUSCRIPT

United States Department of Health and Human Services, Substance Abuse and Mental Health Services

Administration, & Center for Behavioral Health Statistics and Quality. (2012d). National Survey on

Drug Use and Health, 2003. Ann Arbor: Inter-university Consortium for Political and Social

Research.

United States Department of Health and Human Services, Substance Abuse and Mental Health Services

T
Administration, & Center for Behavioral Health Statistics and Quality. (2012e). National Survey on

IP
Drug Use and Health, 2004. Ann Arbor: Inter-university Consortium for Political and Social

CR
Research.

US
United States Department of Health and Human Services, Substance Abuse and Mental Health Services

Administration, & Center for Behavioral Health Statistics and Quality. (2012f). National Survey on
AN
Drug Use and Health, 2005. Ann Arbor: Inter-university Consortium for Political and Social
M

Research.
ED

United States Department of Health and Human Services, Substance Abuse and Mental Health Services

Administration, & Center for Behavioral Health Statistics and Quality. (2012g). National Survey on
PT

Drug Use and Health, 2006. Ann Arbor: Inter-university Consortium for Political and Social

Research.
CE

United States Department of Health and Human Services, Substance Abuse and Mental Health Services
AC

Administration, & Center for Behavioral Health Statistics and Quality. (2012h). National Survey on

Drug Use and Health, 2007. Ann Arbor: Inter-university Consortium for Political and Social

Research.

United States Department of Health and Human Services, Substance Abuse and Mental Health Services

Administration, & Center for Behavioral Health Statistics and Quality. (2013). National Survey on
 ACCEPTED MANUSCRIPT

Drug Use and Health, 2012. Ann Arbor: Inter-university Consortium for Political and Social

Research.

United States Department of Health and Human Services, Substance Abuse and Mental Health Services

Administration, & Center for Behavioral Health Statistics and Quality. (2014a). National Survey on

Drug Use and Health, 2008. Ann Arbor: Inter-university Consortium for Political and Social

T
Research.

IP
CR
United States Department of Health and Human Services, Substance Abuse and Mental Health Services

Administration, & Center for Behavioral Health Statistics and Quality. (2014b). National Survey on

US
Drug Use and Health, 2009. Ann Arbor: Inter-university Consortium for Political and Social

Research.
AN
United States Department of Health and Human Services, Substance Abuse and Mental Health Services
M

Administration, & Center for Behavioral Health Statistics and Quality. (2014c). National Survey on
ED

Drug Use and Health, 2010. Ann Arbor: Inter-university Consortium for Political and Social

Research.
PT

United States Department of Health and Human Services, Substance Abuse and Mental Health Services
CE

Administration, & Center for Behavioral Health Statistics and Quality. (2014d). National Survey on

Drug Use and Health, 2011. Ann Arbor: Inter-university Consortium for Political and Social
AC

Research.

United States Department of Health and Human Services, Substance Abuse and Mental Health Services

Administration, & Center for Behavioral Health Statistics and Quality. (2014e). National Survey on

Drug Use and Health, 2012. Ann Arbor: Inter-university Consortium for Political and Social

Research.
 ACCEPTED MANUSCRIPT

United States Department of Health and Human Services, Substance Abuse and Mental Health Services

Administration, & Center for Behavioral Health Statistics and Quality. (2014f). National Survey on

Drug Use and Health, 2013. Ann Arbor: Inter-university Consortium for Political and Social

Research.

United States Department of Health and Human Services, Substance Abuse and Mental Health Services

T
Administration, & Center for Behavioral Health Statistics and Quality. (2015). National Survey on

IP
Drug Use and Health, 2014. Ann Arbor: Inter-university Consortium for Political and Social

CR
Research.

US
United States Department of Health and Human Services, Substance Abuse and Mental Health Services

Administration, & Center for Behavioral Health Statistics and Quality. (2016). National Survey on
AN
Drug Use and Health, 2014 Ann Arbor, MI: Inter-university Consortium for Political and Social
M

Research.
ED

Valle, M., Maqueda, A. E., Rabella, M., Rodriguez-Pujadas, A., Antonijoan, R. M., Romero, S., & Riba, J.

(2016). Inhibition of alpha oscillations through serotonin-2A receptor activation underlies the visual
PT

effects of ayahuasca in humans. European Neuropsychopharmacology: The Journal of the European

College of Neuropsychopharmacology, 26(7), 1161-1175. doi:10.1016/j.euroneuro.2016.03.012

CE

Volkow, N. D., Koob, G. F., & McLellan, A. T. (2016). Neurobiologic advances from the brain disease
AC

model of addiction. The New England Journal of Medicine, 374(4), 363-371.

doi:10.1056/NEJMra1511480

Vollenweider, F. X., Leenders, K. L., Scharfetter, C., Maguire, P., Stadelmann, O., & Angst, J. (1997).

Positron emission tomography and fluorodeoxyglucose studies of metabolic hyperfrontality and

psychopathology in the psilocybin model of psychosis. Neuropsychopharmacology: Official

 ACCEPTED MANUSCRIPT

Publication of the American College of Neuropsychopharmacology, 16(5), 357-372. doi:S0893-

133X(96)00246-1 [pii]

Vollenweider, F. X., Vollenweider-Scherpenhuyzen, M. F., Bäbler, A., Vogel, H., & Hell, D. (1998).

Psilocybin induces schizophrenia-like psychosis in humans via a serotonin-2 agonist

action. Neuroreport, 9(17), 3897-3902.

T
IP
Vollenweider, F. X., & Kometer, M. (2010). The neurobiology of psychedelic drugs: Implications for the

CR
treatment of mood disorders. Nature Reviews. Neuroscience, 11(9), 642-651. doi:10.1038/nrn2884

Vollenweider, F. X., Vontobel, P., Hell, D., & Leenders, K. L. (1999). 5-HT modulation of dopamine release

US
in basal ganglia in psilocybin-induced psychosis in man--a PET study with
AN
[11C]raclopride. Neuropsychopharmacology: Official Publication of the American College of

Neuropsychopharmacology, 20(5), 424-433. doi:S0893133X98001080 [pii]

M

Walsh, Z., Hendricks, P. S., Smith, S., Kosson, D. S., Thiessen, M. S., Lucas, P., et al. (2016). Hallucinogen
ED

use and intimate partner violence: Prospective evidence consistent with protective effects among

men with histories of problematic substance use. Journal of Psychopharmacology (Oxford,

PT

England), 30(7), 601-607. doi:10.1177/0269881116642538

CE

Wasson, R. G., Hofmann, A., & Ruck, C. A. (1978). The road to Eleusis. Unveiling the Secret of the

Mysteries, New York: Harcourt.

AC

Webster, P. (2000). Mixing the kykeon. Eleusis: Journal of Psychoactive Plants and Compounds, 4, 9-19.

Westermeyer, J. (1988). The pursuit of intoxication: Our 100 century-old romance with psychoactive

substances. The American Journal of Drug and Alcohol Abuse, 14(2), 175-187.

World Health Organization. (2017). Depression [Fact sheet]. Retrieved from

www.who.int/mediacentre/factsheets/fs369/en/
 ACCEPTED MANUSCRIPT

Wolbach, A. B., Isbell, H., & Miner, E. J. (1962a). Cross tolerance between mescaline and LSD-25, with a

comparison of the mescaline and LSD reactions. Psychopharmacologia, 3, 1-14.

Wolbach, A. B., Miner, E. J., & Isbell, H. (1962b). Comparison of psilocin with psilocybin, mescaline and

LSD-25. Psychopharmacologia, 3, 219-223.

Wulff, D. M. (1991). Psychology of religion (1. print. ed.). New York [u.a]: Wiley.

T
IP
Yeo, B. T., Krienen, F. M., Sepulcre, J., Sabuncu, M. R., Lashkari, D., Hollinshead, M., et al. (2011). The

CR
organization of the human cerebral cortex estimated by intrinsic functional connectivity. Journal of

Neurophysiology, 106(3), 1125-1165. doi:10.1152/jn.00338.2011

US
AN
M
ED
PT
CE
AC